ES2718409T3 - Synthesis of polycyclic carbomoylpyridone compounds - Google Patents

Description

DESCRIPTION

Synthesis of polycyclic carbomoylpyridone compounds

BACKGROUND

Field

[0001] New methods of synthesis of polycyclic carbamoylpyridone compounds are described. The intermediates in the synthetic route of the polycyclic carbamoylpyridone compound are also described.

Description of the related technique.

[0002] Human immunodeficiency virus infection and related diseases are a major public health problem worldwide. Type 1 human immunodeficiency virus (HIV-1) encodes three enzymes that are necessary for viral replication: reverse transcriptase, protease and integrase. Although drugs targeting reverse transcriptase and protease are widely used and have proven effective, particularly when used in combination, the toxicity and development of resistant strains have limited their usefulness (Palella, et al. N. Engl. J Med . (1998) 338: 853-860; Richman, DD Nature (2001) 410: 995-1001). Consequently, there is a need for new agents that inhibit HIV replication and that minimize the activation of PXR when co-administered with other medications.

[0003] Certain polycyclic carbamoylpyridone compounds have been found to have antiviral activity, as described in PCT / US2013 / 076367 (publication number WO2014 / 100323). Therefore, there is a need for synthetic routes for such compounds.

SUMMARY

[0004] The present invention is directed to a new synthetic process for preparing the polyammo compounds of carbamoylpyridone of Formula I using the synthetic steps described herein. The present invention is also directed to particular individual steps of this process and to particular individual intermediates used in this process. Formula I:

[0005] An embodiment of the present invention provides a process for preparing a compound of Formula b- 1 • j -1 according to the following scheme:

wherein the process comprises reacting the free acid of b-1 with approximately one to five equivalents of J-1; Y

where

Hal is halogen,

n is 1.2 or 3, and

R ^a is (C ¹ -C ⁴ ) alkyl, aryl (C ² -C ¹⁰ ), or aryl (C ² -C ¹⁰ ) aryl (C ¹ -C ⁴ ).

[0006] Another embodiment provides a process for preparing a salt of formula (3-1 * J-1

wherein the process comprises dissolving the free acid from b-1 and adding an equivalent of J-1,

where

Hal is halogen,

n is 1, 2 or 3,

R ^a is (C ¹ -C ⁴ ) alkyl, aryl (C ⁶ -C ¹⁰ ) or aryl (C ⁶ -C ¹⁰ ) aryl (C ¹ -C ⁴ ).

[0007] Another embodiment of the present invention provides the following structure:

[0008] Another embodiment provides a process for preparing a compound of formula C-1

wherein the process comprises reacting a compound of formula b-1® J-1 with approximately 0.1 to 1 equivalent of a suitable acid, and

where

Hal is halogen, which can be the same or different,

n is 1, 2 or 3, and

R ^a is (C ¹ -C ⁴ ) alkyl, aryl (C ⁶ -C ¹⁰ ) or aryl (C ⁶ -C ¹⁰ ) aryl (C ¹ -C ⁴ ).

[0009] Other embodiments and features will be set forth in the detailed description of the embodiments that follow, and in part it will be apparent from the description, or it can be learned by the practice of the claimed invention. The above summary has been made with the understanding that it should be considered as a brief and general synopsis of some of the embodiments described herein, is provided solely for the benefit and convenience of the reader, and is not intended to limit the scope in any way, or range of equivalents, to which the attached claims are entitled.

DETAILED DESCRIPTION

[0010] In the following description, certain specific details are set forth to provide a complete understanding of various embodiments. However, one skilled in the art will understand that the invention can be practiced without these details. The following description of various embodiments is made with the understanding that the present disclosure should be considered as an example of the claimed subject matter, and is not intended to limit the appended claims to the specific embodiments illustrated. The headings used throughout this disclosure are provided for convenience only and should not be construed as limiting the claims in any way. The embodiments illustrated in any heading can be combined with the embodiments illustrated in any other heading.

Definitions

[0011] Unless the context requires otherwise, throughout the present specification and the claims, the word "comprises" and its variations, such as, "comprises" and "comprising" should be interpreted in an open sense and inclusive, that is "includes, but is not limited to."

[0012] A prefix such as "Cu-v" or (Cu-Cv) indicates that the following group has from u to v carbon atoms. For example, "(C1-C6) alkyl" indicates that the alkyl group has 1 to 6 carbon atoms and aryl (C6-C10) aryl (Ci-Ca) indicates that the aryl portion of the group has 6 to 10 atoms of carbons and the alkyl portion of the group has one to six carbon atoms.

[0013] The reference in this specification to "one embodiment" means that a particular feature, structure or feature described in relation to the embodiment is included in at least one embodiment of the present invention. Therefore, the appearances of the phrase "in one embodiment" in several places throughout this specification do not necessarily refer to the same embodiment. In addition, the particular features, structures or features may be combined in any suitable manner in one or more embodiments.

[0014] "Amino" refers to the radical -NH2.

[0015] "Cyano" refers to the radical -CN.

[0016] "Hydroxy" or "hydroxyl" refers to the radical -OH.

[0017] "Imino" refers to the substituent = NH.

[0018] "Nitro" refers to the radical -NO2.

[0019] "Oxo" refers to the substituent = O.

[0020] "Thioxo" refers to the substituent = S.

[0021] "BzOH" refers to benzoic acid or

[0022] "Alkyl" refers to a linear or branched saturated hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, having one to twelve carbon atoms (C ¹ -C ¹² alkyl), or one to eight carbon atoms (C ¹ -C ⁸ alkyl), or one to six carbon atoms (C ¹ -C ⁶ alkyl), or one to 4 carbon atoms (C ¹ -C ⁴ alkyl) and which is bound to the rest of the molecule by a single bond, for example, methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, ethynyl, propynyl, butynyl, pentinyl, hexinyl, and the like. Unless specifically indicated otherwise in the specification, an alkyl group may be optionally substituted.

[0023] In some embodiments, "alkyl" refers to a linear or branched saturated hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, having one to twelve carbon atoms (C ¹ -C ¹² alkyl) , or one to eight carbon atoms (alkyl C ¹ -C ^8), or one to six carbon atoms (alkyl C ¹ -C ^a), or one to four carbon atoms (alkyl C ¹ -C ⁴ ) and which is attached to the rest of the molecule by a single bond, for example, methyl, ethyl, n-propyl, 1-methylethyl (/ so-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl ( t-butyl), 3-methylhexyl, 2-methylhexyl and the like. Unless specifically indicated otherwise in the specification, an alkyl group may be optionally substituted.

[0024] "Alkenyl" refers to any group derived from a linear or branched hydrocarbon with at least one carbon-carbon double bond. Alkenyl groups include, but are not limited to, ethenyl (vinyl), propenyl (allyl), 1-butenyl, 1,3-butadienyl, and the like. Unless otherwise specified, an alkenyl group has 2 to about 10 carbon atoms, for example 2 to 10 carbon atoms, for example 2 to 6 carbon atoms, for example 2 to 4 carbon atoms .

[0025] "Alkynyl" refers to any group derived from a linear or branched hydrocarbon with at least one carbon-carbon triple bond and includes those groups having a triple bond and a double bond. Examples of alkynyl groups include, but are not limited to, ethynyl (-C = CH), propargyl (-CH ² C = CH), (E) -pent-3-en-1-inyl, and the like. Unless otherwise specified, an alkynyl group has from 2 to about 10 carbon atoms, for example from 2 to 10 carbon atoms, for example from 2 to 6 carbon atoms, for example from 2 to 4 carbon atoms .

[0026] "Alkoxy" refers to a radical of the formula -OR ^A where R ^A is an alkyl radical as defined above containing one to twelve carbon atoms, or one to eight carbon atoms, or one to six carbon atoms, or one to four carbon atoms. Unless specifically indicated otherwise in the specification, an alkoxy group may be optionally substituted.

[0027] "Alkylamino" refers to a radical of the formula -NHR ^A or -NR ^A R ^A where each R ^A is independently an alkyl radical as defined above containing one to twelve carbon atoms, or of one to eight carbon atoms, or one to six carbon atoms, or one to four carbon atoms. Unless specifically indicated otherwise in the specification, an alkylamino group may be optionally substituted.

[0028] "Thioalkyl" refers to a radical of the formula -SR ^A where R ^A is an alkyl radical as defined above containing one to twelve carbon atoms, or one to eight carbon atoms, or one to six carbon atoms, or one to four carbon atoms. Unless specifically indicated otherwise in the specification, a thioalkyl group may be optionally substituted.

[0029] "Aryl" refers to a monocyclic hydrocarbon ring system radical comprising hydrogen and 6 to 18 carbon atoms, or 6 to 10 carbon atoms or 6 to 8 carbon atoms. Aryl radicals include, but are not limited to, aryl radicals derived from benzene. Unless specifically indicated otherwise in the specification, the term "aryl" or the prefix "ar-" (as in "aralkyl") is intended to include aryl radicals that are optionally substituted.

[0030] "Arylalkyl" (also "aralkyl") refers to a radical of the formula -R ^B -R ^C where R ^B is an alkyl group as defined above and R ^c is one or more aryl radicals as defined above. , for example, benzyl. Arylalkyl groups include, but are not limited to, those groups derived from benzyl, tolyl, dimethylphenyl, 2-phenylethane-1-yl, 2-naphthylmethyl, phenylmethylbenzyl, 1,2,3,4-tetrahydronaphthyl, and the like. An arylalkyl group comprises from 6 to about 30 carbon atoms, for example, the alkyl group may comprise from 1 to about 10 carbon atoms and the aryl group may comprise from 5 to about 20 carbon atoms. Unless specifically indicated otherwise in the specification, an aralkyl group may be optionally substituted.

[0031] In some embodiments, "arylalkyl" (also "aralkyl") refers to a radical of the formula -R ^B -R ^C where R ^B is an alkyl group as defined above and R ^c is one or more aryl radicals as defined above, for example benzyl. Arylalkyl groups include, but are not limited to, those groups derived from benzyl, tolyl, dimethylphenyl, 2-phenylethane-1-yl, 2-naphthylmethyl, phenylmethylbenzyl, 1,2,3,4-tetrahydronaphthyl, and the like. An arylalkyl group comprises from 6 to about 30 carbon atoms, for example, the alkyl group may comprise from 1 to about 10 carbon atoms and the aryl group may comprise from 6 to about 20 carbon atoms. Unless specifically indicated otherwise in the specification, an aralkyl group may be optionally substituted.

[0032] "Cycloalkyl" refers to a cyclic alkyl group. A cycloalkyl group may have one or more cyclic rings and includes fused and bridged groups. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl and the like. Unless specifically indicated otherwise in the specification, a carbocyclic group may be optionally substituted.

[0033] "Carbocyclic ring" or "carbocycle" refers to a stable non-aromatic monocyclic hydrocarbon radical which It consists solely of carbon and hydrogen atoms, which has three to fifteen carbon atoms, preferably three to ten carbon atoms, and which is saturated or unsaturated and attached to the rest of the molecule by a single bond. Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Unless specifically indicated in the specification, a carbocyclic group may be optionally substituted.

[0034] "Cycloalkylalkyl" refers to a radical of the formula -RbRd where RB is an alkyl group as defined above and RD is a carbocyclic radical as defined above. Unless specifically indicated otherwise in the specification, a cycloalkylalkyl group may be optionally substituted.

[0035] In some embodiments, "cycloalkylalkyl" refers to a radical of the formula -RbRd where RB is an alkyl group as defined above and RD is a carbocyclic radical as defined above. Unless specifically indicated otherwise in the specification, a cycloalkylalkyl group may be optionally substituted.

[0036] "Halo" or "halogen" refers to bromine, chlorine, fluorine or iodine.

[0037] "Haloalkyl" refers to an alkyl radical, as defined above, which is substituted with one or more halo radicals, as defined above, for example, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl , 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl and the like. Unless specifically indicated otherwise in the specification, a haloalkyl group may be optionally substituted.

[0038] "Heterocyclyl" or "heterocyclic ring" refers to a stable non-aromatic ring radical of 3 to 18 members consisting of two to twelve carbon atoms and one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. In some embodiments, the heterocyclyl radical is a non-aromatic ring of 3 to 12 members, or a non-aromatic ring of 3 to 8 members, or a non-aromatic ring of 3 to 6 members. In some embodiments, the heterocyclyl radical contains one to four heteroatoms, or one to three heteroatoms, or one to two heteroatoms, or a heteroatom. In the embodiments described herein, the heterocyclyl radical is a monocyclic ring system; and the heterocyclyl radical may be partially or fully saturated. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl, [1,3] dithianyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, pyropyrazidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydro-furyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl and 1,1-dioxo-thiophorpholinyl unless specifically stated otherwise, specifically specified heterocyclyl group may be optionally substituted.

[0039] In some embodiments, "heterocyclyl" or "heterocyclic ring" refers to a stable 4 to 18 membered non-aromatic ring radical consisting of 3 to 17 carbon atoms and one to six heteroatoms selected from the group consisting of in nitrogen, oxygen and sulfur. In some embodiments, the heterocyclyl radical is a non-aromatic ring of 4 to 12 members, or a non-aromatic ring of 4 to 8 members, or a non-aromatic ring of 4 to 6 members. In some embodiments, the heterocyclyl radical contains one to four heteroatoms, or one to three heteroatoms, or one to two heteroatoms, or a heteroatom. Unless specifically indicated otherwise in the specification, a heterocyclyl group may be optionally substituted.

[0040] "W-heterocyclyl" refers to a heterocyclyl radical as defined above that contains at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical . Unless specifically indicated otherwise in the specification, a W-heterocyclyl group may be optionally substituted.

[0041] "Heterocyclylalkyl" refers to a radical of the formula -R ^b R ^e where RB is an alkyl group as defined above and Re is a heterocyclyl radical as defined above, and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl can be attached to the alkyl radical in the nitrogen atom. Unless specifically indicated otherwise in the specification, a heterocyclylalkyl group may be optionally substituted.

[0042] "Heteroaryl" refers to an aryl group in which one or more of the carbon atoms (and any associated hydrogen atom) are each independently replaced with the same or different heteroatom selected from the group consisting of nitrogen, oxygen and sulfur. Unless otherwise specified, a heteroaryl group has 5 to about 20 carbon atoms, for example 5 to 18 carbon atoms, for example 5 to 14 carbon atoms, for example 5 to 10 carbon atoms . Heteroaryl groups have one to six heteroatoms, one to four heteroatoms, one to three heteroatoms, one to two heteroatoms or a heteroatom. Unless specifically indicated otherwise in the specification, a heteroaryl group may be optionally substituted.

[0043] In some embodiments, "heteroaryl" refers to an aryl group in which one or more of the carbon atoms (and any of the associated hydrogen atoms) are each independently replaced with the same or different heteroatom selected from the group consisting of nitrogen, oxygen and sulfur. The groups heteroaryl include, but are not limited to, groups derived from furan, imidazole, isothiazole, isoxazole, oxadiazole, oxazol, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrolo, tetrazole, thiadiazole, thiazole, thiophene, triazole, and the like. Unless otherwise specified, a heteroaryl group has 5 to about 20 carbon atoms, for example 5 to 18 carbon atoms, for example 5 to 14 carbon atoms, for example 5 to 10 carbon atoms . Heteroaryl groups have one to six heteroatoms, one to four heteroatoms, one to three heteroatoms, one to two heteroatoms or a heteroatom. Unless specifically indicated otherwise in the specification, a heteroaryl group may be optionally substituted.

[0044] "W-heteroaryl" refers to a heteroaryl radical as defined above that contains at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. . Unless specifically indicated otherwise in the specification, a W-heteroaryl group may be optionally substituted.

[0045] "Heteroarylalkyl" refers to a radical of the formula -R ^b R ^f where R ^B is an alkyl group as defined above and R ^f is a heteroaryl radical as defined above. Unless specifically indicated otherwise in the specification, a heteroarylalkyl group may be optionally substituted.

[0046] The term "substituted" used herein means any of the above groups (ie, alkyl, alkylene, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, carbocycle, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocycle, heterocycle, heteroaryl, N-heteroaryl and / or heteroarylalkyl) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atom such as, but not limited to: a halogen atom, such as F, Cl, Br e I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups and ester groups; a sulfur atom in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylamines, diarylamines, N-oxides, imides and enamines; a silicon atom in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldyrylsilyl groups and triarylsilyl groups; and other heteroatoms in other groups. "Substituted" also means any of the above groups in which one or more hydrogen atoms are replaced by a higher order bond (eg, a double or triple bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl and ester groups; and nitrogen in groups such as imines, oximes, hydrazones and nitriles. For example, "substituted" includes any of the above groups in which one or more hydrogen atoms are replaced with - NR ^g R ^h , -NR ^g C (= 0) R ^h , -NR ^g C (= 0) NR ^g R ^h , -NR ^g C (= 0) OR ^h , -NR ^G C (= NR ^g ) NR ^G R ^H , -NR ^g S0 ² R ^h , -OC (= 0) NR ^g R ^h , -OR ^g, -SR ^g, -SOR ^g, -SO ² R ^g, -OSO ² R ^g, -SO ² OR ^g, = NS0 ² R ^g, and -S0 ² NR ^g R ^h. "Substituted also means any of the above groups in which one or more hydrogen atoms are replaced with -C (= 0) R ^g , -C (= 0) OR ^g , -C (= 0) NR ^g R ^h , -CH ² SO ² R ^G , -CH ² SO ² NR ^G R ^H In the foregoing, R ^g and R ^h are the same or different and independently hydrogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, carbocycle, cycloalkylalkyl , haloalkyl, heterocyclyl, W-heterocyclyl, heterocyclylalkyl, heteroaryl, W-heteroaryl and / or heteroarylalkyl. "Substituted" further means any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano , hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, carbocycle, cycloalkylalkyl, haloalkyl, heterocyclyl, W-heterocyclyl, heterocyclylalkyl, heteroaryl, W-heteroaryl and / or heteroaryl. , each of the above substituents may also be optional mind substituted with one or more of the above substituents.

[0047] The term "alkylated formamide acetal", as used herein, refers to a compound of Formula:

wherein each R ^B is independently (C ¹ -C ⁴ ) alkyl, R ^v1 and R ^v2 are independently (C ¹ -C ⁶ ) alkyl or R ^v1 and R ^v2 together with the atoms to which they are attached form a heterocyclyl of 5 to 10 members.

[0048] "Alkylated formamide acetal" includes, but is not limited to, W, W-dimethylformamide dimethyl acetal, W, W- dimethylformamide diethyl acetal, W, W-dimethylformamide diisopropylacetal, W, W-diethylformamide dimethyl acetal, and W , W- diisopropylformamide dimethyl acetal.

[0049] The term "acyl donor", as used herein, refers to a reactive compound that transfers a -CO-R ^{x group} to another molecule, where R ^x is alkyl (C ¹ -C ⁶⁾ ) -R ^y and R ^and is selected from the group consisting of H, CN, -NR ^z1 R ^z2 , C (O) R ^z1 , - C (O) OR ^z1 , -C (O) NR ^z1 R ^z2 , - OC (O) NR ^z1 R ^z2 , -NR ^z1 C (O) R ^z2 , -NR ^z1 C (O) NR ^z2 , -NR ^Z1 C (O) OR ^z2 , -SR ^z1 , -S (O) ^{1- 2} R ^z1 , -S (O) ² NR ^z1 R ^z2 , -NR ^z1 S (O) z ² , NR ^z1 S (O) ² R ^z2 and OR ^z1 . R ^z1 and R ^z2 are selected independently from the group consisting of H, C ^1-6 alkyl, C ^2-6 alkenyl, C ^2-6 alkynyl, heteroalkyl C ^1-6 cycloalkyl C ^3-10, 3 to 12 member heterocyclyl, C ^6-10 heteroaryl and 5 to 10 member heteroaryl. In certain embodiments, R ^and is H. In certain embodiments, R ^z1 and R ^z2 are independently selected from the group consisting of H and C ^1-6 alkyl. Acyl donors include, among others, anhydrides, esters and acid chlorides such as succinic anhydride, glutaric anhydride, acetic anhydride, vinyl acetate, isopropenyl acetate, 4-chlorophenyl acetate, ethylmethoxy acetate, acetyl chloride and chloride of benzoyl.

[0050] A person skilled in the art will understand that throughout this application, and more specifically in Schemes I, II, III, V and VI, compound E-1 may exist in an E or Z configuration or as a mixture of an E and Z configuration. Accordingly, in certain embodiments, the compound E-1 is in an E or Z configuration, or a mixture thereof. In certain embodiments, compound E-1 is in an E configuration. In certain embodiments, compound E-1 is in a Z configuration. In certain embodiments, compound E-1 is in a mixture of Z and E configurations.

[0051] One skilled in the art will understand that throughout this application, compound b-1.J-1 is a salt:

[0052] The term "protecting group", as used herein, refers to a labile chemical moiety known in the art to protect reactive groups that include, without limitation, hydroxyl and amino groups, against non-reaction. desired during synthetic procedures. The hydroxyl and amino groups protected with a protecting group are referred to herein as "protected hydroxyl groups" and "protected amino groups," respectively. Protective groups are typically used selectively and / or orthogonally to protect sites during reactions at other reactive sites and can then be removed to leave the group unprotected as is or available for other reactions. Protective groups as are known in the art are generally described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). In general, the groups are protected or presented as a precursor that will be inert to reactions that modify other areas of the parental molecule for conversion into their final groups at an appropriate time. Other representative protecting groups or precursors are discussed in Agrawal, et al., Protocols for Oligonucleotide Conjugates, Eds, Humana Press; New Jersey, 1994; Vol. 26 pp. 1-72. Examples of "hydroxyl protecting groups" include, but are not limited to, t-butyl, t-butoxymethyl, methoxymethyl, tetrahydropyranyl, 1-ethoxyethyl, 1- (2-chloroethoxy) ethyl, 2-trimethylsilylethyl, p-chlorophenyl, 2,4-Dinitrophenyl, benzyl, 2,6-dichlorobenzyl, diphenylmethyl, p-nitrobenzyl, triphenylmethyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl (TBDPS), triphenylsilyl, benzoylformacetate, trichloroacetate, triochloroacetate, acetate, chloroacetoacetate, acetate, chloroacetoacetate, acetate, chloroacetoacetate, acetate, chloroacetoacetate, acetate, chloroacetoacetate, acetate, trichloroacetate acetate , benzoate, phenylbenzoate, 9-fluorenylmethyl carbonate, mesylate and tosylate. Examples of "amino protecting groups" include, but are not limited to, carbamate protecting groups, such as 2-trimethylsilylethoxycarbonyl (Teoc), 1-methyl-1- (4-biphenylyl) ethoxycarbonyl (Bpoc), t-butoxycarbonyl (BOC), allyloxycarbonyl (Alloc), 9-fluorenylmethyloxycarbonyl (Fmoc) and benzyloxycarbonyl (Cbz); amide protecting groups, such as formyl, acetyl, trihaloacetyl, benzoyl and nitrophenylacetyl; sulfonamide protecting groups, such as 2-nitrobenzenesulfonyl; and cyclic imide and imide protecting groups, such as phthalimide and dithiasuccinoyl.

[0053] The invention described herein is also intended to encompass all compounds. Pharmaceutically acceptable Formula I and compounds of Formula II that are isotopically labeled by having one or more atoms replaced by an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the described compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ³⁶ Cl ¹²³ I and ¹²⁵ I, respectively. These radiolabeled compounds could be useful to help determine or measure the effectiveness of the compounds, characterizing, for example, the site or mode of action, or the affinity of binding to a pharmacologically important site of action. Certain compounds labeled with isotopes of Formula I and compounds of Formula II, for example, those that incorporate a radioactive isotope, are useful in tissue distribution studies of substrates and / or drugs. Tritium radioactive isotopes, that is, ³ H, and carbon-14, that is, ¹⁴ C, are particularly useful for this purpose in view of their ease of incorporation and available detection means.

[0054] Substitution with heavier isotopes, such as deuterium, that is, ² H, may provide certain therapeutic advantages resulting from increased metabolic stability. For example, the half-life in vivo may increase or the dosage requirements may be reduced. Therefore, heavier isotopes may be preferred in some circumstances.

[0055] Substitution with positron-emitting isotopes, such as ¹¹ C, ¹⁸ F, ¹⁵ O, and ¹³ N, may be useful in Positron Emission Topography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of Formula I and compounds of Formula II can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples set forth below, using an isotopically labeled reagent in place. of the unlabeled reagent previously used.

[0056] The invention described herein is also intended to encompass in vivo metabolic products of the described compounds. Such products may result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification and the like of the compound administered, mainly due to enzymatic processes. Accordingly, the invention includes compounds produced by a process comprising administering a compound of this invention to a mammal for a period of time sufficient to produce a metabolic product thereof. Such products are typically identified by administering a radiolabeled compound described in the embodiments of this document in a detectable dose to an animal, such as rat, mouse, guinea pig, monkey or human, which allows sufficient time for metabolism to occur and isolates its conversion. . Products from urine, blood or other biological samples.

[0057] "Stable compound" and "stable structure" are intended to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity of a reaction mixture, and formulation in an effective therapeutic agent.

[0058] "Lewis acid" refers to a group that can accept a pair of non-bonding electrons, that is, an electron pair acceptor. Lewis acids can react with a Lewis base to form a Lewis adduct, sharing the electron pair supplied by the Lewis base.

[0059] "Mammal" includes human beings and domestic animals such as laboratory animals and domestic pets (eg, cats, dogs, pigs, cows, sheep, goats, horses, rabbits) and non-domestic animals such as wildlife and Similar.

[0060] "Optional" or "optionally" means that the event of circumstances described below may or may not occur, and that the description includes cases in which said event or circumstance occurs and cases in which it does not occur. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted and that the description includes both the substituted aryl radicals and the aryl radicals that have no substitution.

[0061] The "pharmaceutically acceptable carrier, diluent or excipient" includes, without limitation, any adjuvant, carrier, excipient, slider, sweetener, diluent, preservative, dye / dye, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that has been approved by the United States Food and Drug Administration as acceptable for use in humans or pets.

[0062] "Pharmaceutically acceptable salt" refers to a salt of a compound that is pharmaceutically acceptable and that possesses (or can become a form that possesses) the desired pharmacological activity of the original compound. Examples of "pharmaceutically acceptable salts" of the compounds described herein include salts derived from an appropriate base, such as an alkali metal (eg, sodium), an alkaline earth metal (eg, magnesium), ammonium and NX ⁴⁺ (where X is C ¹ -C ⁴ alkyl). Pharmaceutically acceptable salts of a nitrogen atom or an amino group include, for example, salts of organic carboxylic acids such as acetic, benzoic, camphorsulfonic, citric, glucoheptonic, gluconic, lactic, fumaric, tartaric, maleic, malonic, malic, Mandelic, isethionic, lactobionic, succinic, 2-naphthalenesulfonic, oleic, palmitic, propionic, stearic and trimethylacetic; organic sulfonic acids, such as methanesulfonic acids, ethanesulfonic acids, benzenesulfonic and p-toluenesulfonic; and inorganic acids, such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric and sulfamic acids. Pharmaceutically acceptable salts of a compound of a hydroxy group include the anion of said compound in combination with a suitable cation such as Na ⁺ and NX ⁴⁺ (wherein X is independently selected from H or a C ¹ -C ⁴ alkyl group) . Pharmaceutically acceptable salts also include salts formed when an acid proton present in the original compound is replaced by a metal ion, for example, an alkali metal ion, an alkaline earth ion or an aluminum ion; or is coordinated with an organic base such as diethanolamine, triethanolamine, N-methylglucamine and the like. Also included in this definition are ammonium salts and quaternized or substituted ammonium salts. Representative non-limiting lists of pharmaceutically acceptable salts can be found in SM Berge et al., J. Pharma Sci., 66 (1), 1 19 (1977) and Remington: The Science and Practice of Pharmacy, R Hendrickson, ed., Edition 21, Lippincott, Williams & Wilkins, Philadelphia, PA, (2005), on p. 732, Table 38-5, which are incorporated herein by reference in this document.

[0063] For therapeutic use, the salts of the active ingredients of the compounds described herein will typically be pharmaceutically acceptable, that is, they will be salts derived from a physiologically acceptable acid or base. However, salts of acids or bases that are not pharmaceutically acceptable may also be useful, for example, in the preparation or purification of a compound of Formula I, a compound of Formula II or another compound described herein. All salts, whether or not derived from a physiologically acceptable acid or base, are within the scope of the present invention.

[0064] Metal salts refer to salts in which the cation is a metal, such as those formed when an acid proton present in a compound is replaced by a metal ion, for example, an alkali metal ion, an ion alkaline earth or an aluminum ion; or a coordinate of metal ions with an organic base such as diethanolamine, triethanolamine, N-methylglucamine and the like.

[0065] The metal may be an alkali metal, an alkaline earth metal, a transition metal or a metal of the main group. Non-limiting examples of suitable metals include lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium and zinc.

[0066] Non-limiting examples of suitable metal salts include a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, a salt of iron, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt and a zinc salt.

[0067] In addition, salts may be formed from the addition of acids of certain organic and inorganic acids, for example, HCl, HBr, H ² SO ⁴ , H ³ PO ⁴ or sulfonic organic acids, to basic centers, typically amines .

[0068] Finally, it should be understood that the compositions herein comprise compounds described herein in their ionized form, as well as zwitterionic, and combinations with stoichiometric amounts of water as in hydrates.

[0069] Often crystallizations produce a solvate of the compound described in the embodiments described herein. As used herein, the term "solvate" refers to an aggregate comprising one or more molecules of a compound described herein with one or more solvent molecules. The solvent can be water, in which case the solvate can be a hydrate. Alternatively, the solvent may be an organic solvent. Therefore, the compounds of the present invention may exist as a hydrate, which includes a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms. The compounds described herein may be true solvates, while in other cases, the compound described herein may simply retain adventitious water or be a mixture of water plus some adventitious solvent.

[0070] A "pharmaceutical composition" refers to a formulation of a compound described herein and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, for example, humans. Said medium includes all pharmaceutically acceptable carriers, diluents or excipients.

[0071] "Effective amount" or "therapeutically effective amount" refers to an amount of a compound according to the invention, which when administered to a patient in need, is sufficient to effect the treatment of disease states, conditions or disorders so that the compounds have utility. Such amount would be sufficient to elicit the biological or medical response of a tissue system or patient seeking a researcher or clinician. The amount of a compound according to the invention that constitutes a therapeutically effective amount will vary depending on factors such as the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of excretion. of the compound, the duration of treatment, the type of disease or disorder being treated and its severity, the medications used in combination or coincidentally with the compounds described in this document, and the age, body weight, general health, sex and diet of the patient. Such therapeutically effective amount It can be routinely determined by a person skilled in the art taking into account his own knowledge, the state of the art and this disclosure.

[0072] The term "treatment", as used herein, is intended to mean the administration of a compound or composition according to the present invention to alleviate or eliminate the symptoms of HIV infection and / or to reduce viral load. in a patient The term "treatment" also encompasses the administration of a compound or composition according to the present invention after exposure of the individual to the virus, but before the onset of disease symptoms and / or before the detection of the virus in the blood, to prevent the onset of symptoms of the disease and / or to prevent the virus from reaching detectable levels in the blood, and the administration of a compound or composition according to the present invention to prevent perinatal HIV transmission of the mother to baby, by administration to the mother before delivery and the child in the first days of life.

[0073] The term "antiviral agent", as used herein, is intended to mean an agent (compound or biological) that is effective in inhibiting the formation and / or replication of a virus in a human being, including, among others, agents that interfere with either the host or the viral mechanisms necessary for the formation and / or replication of a virus in a human being.

[0074] The term "HIV replication inhibitor", as used herein, is intended to mean an agent capable of reducing or eliminating the ability of HIV to replicate in a host cell, whether in vitro, ex vitro or in vitro. alive.

[0075] The compounds described herein, or their pharmaceutically acceptable salts, may contain one or more asymmetric centers and, therefore, may give rise to enantiomers, diastereomers and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R) - or (S) - or, as (D) - or (L) - for amino acids. The present invention is intended to include all possible isomers, as well as their racemic and optically pure forms. The optically active isomers (+) and (-), (R) - and (S) -, or (D) - and (L) - can be prepared using chiral syntons or chiral reagents, or can be resolved using conventional techniques, for example , chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or a derivative) using, for example, chiral high pressure liquid chromatography ( HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, the compounds are intended to include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended for be included

[0076] A "stereoisomer" refers to a compound formed by the same atoms linked by the same bonds but having different three-dimensional structures, which are not interchangeable. The present invention contemplates several stereoisomers and mixtures thereof and includes "enantiomers", which refers to two stereoisomers whose molecules are mirror images not superimposable on each other.

[0077] A "tautomer" refers to a change of protons from one atom of a molecule to another atom of the same molecule. The present invention includes tautomers of any of said compounds.

[0078] An "enantio enriched" compound refers to a compound that contains more than 50% of one of a pair of enantiomers. A compound "enanti enriched" may have an enantiomeric excess (% ee) greater than 5%, greater than 10%, greater than 20%, greater than 30%, greater than 50%, greater than 60%, greater than 70% , greater than 80%, more than 90%, more than 95%, more than 99% or more than 99.9%.

[0079] The reference to "approximately" a value or parameter in this document includes (and describes) embodiments that address that value or parameter itself. For example, the description that refers to "about X" includes the description of "X". In addition, the singular forms "a", "a", "the" and "she" include plural references, unless the context clearly indicates otherwise. Thus, for example, the reference to "the compound" includes a plurality of said compounds and the reference to "the assay" includes a reference to one or more assays and equivalents thereof known to those skilled in the art.

General Schemes

[0080] Certain embodiments are directed to the general multistage synthetic methods described below, namely, General Schemes I-VI. All substituent groups in the steps described below are defined below:

Hal is halogen,

n is 1, 2 or 3,

L is -C (R ^c ) ² -, -C (R ^c ) ² C (R ^c ) ² -, -C (R ^c ) ² C (R ^c ) ² C (R ^c ) ² -, or - C (R ^c ) ² C (R ^c ) ² C (R ^c ) ² C (R ^c ) ² -,

each R ^c is independently hydrogen, halo, hydroxyl or C ¹ -C ⁴ alkyl,

each R ^a , R ^b , R ^d , R ¹ and R ² is independently alkyl, aryl or aralkyl.

[0081] In some embodiments, Hal is halogen, which may be the same or different.

[0082] In certain embodiments, each R ^a , R ^b , R ^d , R ¹ and R ² is, independently, (C ¹ -C ⁴ ) alkyl, aryl (C ² -C ¹⁰ ) or aryl (C ² -C ¹⁰ ) (C ¹ -C ⁴ ) alkyl.

[0083] In some embodiments, each R ^a , R ^b , R ¹ and R ² is, independently, (C ¹ -C ⁴ ) alkyl, aryl (C ⁶ -C ¹⁰ ) or aryl (C ¹ -C ¹⁰ ) aryl (C ¹ -C ⁴ ).

[0084] In certain embodiments, each R ^b is independently (C ¹ -C ⁴ ) alkyl.

[0085] In certain embodiments, each R ^c is independently hydrogen, -F, -Cl, hydroxyl or methyl. In a certain embodiment, each R ^c is independently hydrogen, -F or -Cl. In certain embodiments, each R ^c is hydrogen.

[0086] In certain embodiments, each R ^a , R ^b , R ^d , R ¹ and R ² is independently methyl, ethyl, phenyl or benzyl. In certain embodiments, each R ^a , R ^b , R ¹ and R ² is methyl. In particular embodiments, R ^d is ethyl.

[0087] In certain embodiments, each R ¹ is C ¹ -C ⁴ alkyl and each R ¹ , together with the atoms to which they are attached, forms a heterocycle. In certain embodiments, each R ¹ is methyl or ethyl, and each R ¹ , together with the atoms to which they are attached, forms a heterocycle. In certain embodiments, each R ¹ is methyl, and each R ¹ , together with the atoms to which they are attached, forms a heterocycle.

General scheme I:

[0088] In certain embodiments, a process is provided in accordance with general scheme I:

in which the process includes the following steps:

by reacting C-1 with an alkylated formamide acetal to obtain D-1;

by reacting D-1 with K-1 to produce E-1;

by reacting E-1 with M-1 in the presence of a base to obtain F-1;

by reacting F-1 with at least one acid and N-1, or salts or co-crystals thereof, in the presence of a base to give G-1;

by reacting G-1 under suitable conditions to produce a compound of Formula I.

[0089] In some embodiments, N-1 is in the form of a salt or a co-crystal.

General scheme II:

[0090] In certain embodiments, a process is provided in accordance with general scheme I:

in which the process includes the following steps:

reacting A-1 with H-1 in the presence of a catalyst, a base and an acylation reagent to obtain b-1;

reacting b-1 with J-1 in the presence of an acid to produce C-1;

react C-1 with an alkylated formamide acetal to obtain D-1;

react D-1 with K-1 to produce E-1;

react E-1 with M-1 in the presence of a base to obtain F-1;

react F-1 with at least one acid and N-1 in the presence of a base to obtain G-1; reacting G-1 under suitable conditions produces a compound of Formula I.

[0091] In some embodiments, J-1 is in the form of a salt or a co-crystal.

[0092] In some embodiments, N-1 is in the form of a salt or a co-crystal.

General scheme III:

[0093] In certain embodiments, a process is provided in accordance with general scheme I:

in which the process includes the following steps:

react b-1 with Q-1 to produce BB-1

react BB-1 with J-1 to produce C-1;

react C-1 with an alkylated formamide acetal to obtain D-1;

react D-1 with K-1 to produce E-1;

react E-1 with M-1 in the presence of a base to obtain F-1;

reacting F-1 with at least one acid and N-1, or salts or co-crystals thereof, in the presence of a base to give G-1;

react G-1 under suitable conditions to produce a compound of Formula I.

[0094] In some embodiments, J-1 is in the form of a salt or a co-crystal.

General scheme IV:

[0095] In certain embodiments, a process is provided in accordance with general scheme I:

in which the process includes the following steps:

by reacting C-1 with an alkylated formamide acetal to obtain D-1;

by reacting D-1 with M-1 to produce EE-1;

by reacting EE-1 with K-1 to obtain F-1;

by reacting F-1 with at least one acid and N-1, in the presence of a base to produce G-1; by reacting G-1 under suitable conditions to produce a compound of Formula I.

[0096] In some embodiments, N-1 is in the form of a salt or a co-crystal.

General scheme V

[0097] In certain embodiments, a process is provided in accordance with general scheme I:

in which the process includes the following steps:

react C-1 with an alkylated formamide acetal to obtain D-1;

react D-1 with K-1 to produce E-1;

react E-1 with M-1 in the presence of a base to obtain F-1;

react F-1 with a base to produce a compound of Formula II.

General scheme VI

[0098] In certain embodiments, a process is provided in accordance with general scheme I:

in which the process includes the following steps:

react b-1.J-1 under conditions suitable to produce C-1;

react C-1 with an alkylated formamide acetal to obtain D-1;

react D-1 with K-1 to produce E-1;

react E-1 with M-1 in the presence of a base to obtain F-1;

by reacting F-1 with at least one acid to produce FF-1;

by reacting FF-1 with N-1, or salts or co-crystals thereof, in the presence of an additive to produce G-1;

react G-1 under suitable conditions to produce a compound of Formula I.

[0099] In some embodiments, reacting F-1 with at least one acid produces the following aldehyde:

It hydrates to give FF-1.

General scheme VII

[0100] Certain embodiments are directed to the synthetic multi-stage method described below, namely, General Scheme VII:

in which the process includes the following steps:

hydrogenate (-) - Lactamic vince and protecting the reduced product to obtain a-1;

react a-1 with R3-M to produce b-1;

oxidize b-1 and hydrolyze the oxidation product to produce c-1.

[0101] In the general scheme VII:

PG is a protective group; Y

R3M is a Grignard n-alkyl reagent or an alkyl organolithium reagent.

[0102] In certain embodiments, the protecting group (PG) is selected from the group consisting of Boc, phthalimide, benzyl, FMoc, acetyl, triphenylmethyl, trifluoroacetyl, benzylidene, p-toluenesulfonamide, p-methoxybenzyl carbonyl, benzoyl, p-methoxybenzyl , carbamates, 3,4-dimethoxybenzyl, p-methoxyphenyl, sulfonamides and carbobenzyloxy. In particular embodiments, the protective group is Boc.

[0103] In certain embodiments, R3M is an ethyl magnesium halide, an n-propylmagnesium halide and a n-butyl magnesium halide, lithium methyl, n-butyllithium or n-hexyl lithium. In particular embodiments, R3M is methyl magnesium bromide. Scheme VIII

[0104] Certain embodiments are directed to the synthetic multi-stage method described below, namely Scheme VIII:

where the process includes the following steps:

react g-lx under effective conditions to produce h-1x; Y

react h-lx under effective conditions to produce N-lx.

[0105] In some embodiments, the process further comprises the following step:

react F-1x under effective conditions to produce g-lx.

[0106] In some embodiments, g-lx is hydrogenated in the presence of a catalyst and a source of hydrogen to produce h-lx.

[0107] In some embodiments, the catalyst is selected from the group consisting of catalysts based on palladium (Pd), PtO ² , Raney nickel, RhCl (PPh ³ ) ³ , Nyori catalyst and Crabtree catalyst. Examples of palladium catalyst include Pd / C. In some embodiments, the catalyst is selected from the group consisting of Pd / C, PtO ² , Raney nickel, RhCl (PPh ³ ) ³ , Nyori catalyst and Crabtree catalyst. In some embodiments, the catalyst is PtO ² .

[0108] In certain embodiments, the source of hydrogen is formic acid, hydrazine, dihydronaphthalene, dihydroanthramene, H ² gas or Hantzch ester and isopropanol. In particular embodiments, the source of hydrogen is H ² gas. In particular embodiments, the source of hydrogen is H ² gas under a hydrogen atmosphere.

[0109] In some embodiments, h-lx is reacted with an acid to produce N-lx. In some embodiments, the acid is a sulfonic acid, which includes, among others, methanesulfonic acid, p-toluenesulfonic acid and camphorsulfonic acid; an inorganic acid, which includes but is not limited to phosphoric acid, hydrochloric acid and sulfuric acid; a carboxylic acid that includes, among others, trifluoroacetic acid, oxalic acid and benzoic acid. In certain embodiments, the acid is an inorganic acid. In particular embodiments, the acid is hydrochloric acid. In particular embodiments, the acid is anhydrous hydrochloric acid.

[0110] In some embodiments, g-lx is

and N-lx is

[0111] In some embodiments, F-1x is

Scheme IX

[0112] Certain embodiments are directed to the synthetic multi-stage method described below, namely, General Scheme IX:

in which the process includes the following steps:

reacting racemic c-(which is a mixture of cc-1b and cc-la) with an acyl donor and an enzyme to produce cc-1b and e-1;

isolate cc-lb e-1; Y

Hydrolyze e-1 to obtain cc-enantio enriched.

[0113] In certain embodiments, Rx is (Ci-C6) -Ry alkyl and Ry is selected from the group consisting of H, CN, -NRz1Rz2, C (O) Rz1, -C (O) ORz1, -C (O ) NRz1Rz2, - OC (O) NRz1Rz2, -NRz1C (O) Rz2, -NRz1C (O) NRz2, -NRz1C (O) ORz2, -SRz1, -S (O) 1-2Rz1, -S (O) 2NRz1Rz2- NRz1S (O) 2Rz2, NRz1S (O) 2Rz2 and ORz1.

[0114] In certain embodiments, Rz1 and Rz2 are independently selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1.6 heteroalkyl, C3.10 cycloalkyl, C3.10 heterocycle, C6-10 aricyl and 5-10 membered heteroaryl.

[0115] In certain embodiments, Rx is (C1-C6) alkyl -Ry and Ry is selected from the group consisting of H, -C (O) ORz1 and Rz1 is selected from the group consisting of H, C1-6 alkyl, C3-10 cycloalkyl and 3 to 12 membered heterocyclyl.

[0116] In certain embodiments, Rx is (C1-C6) alkyl -Ry and Ry is selected from the group consisting of H, -C (O) ORz1 and Rz1 is selected from the group consisting of H and C1-6 alkyl.

[0117] In certain embodiments, Rx is (C1-C4) alkyl -Ry and Ry is selected from the group consisting of H and CO2H.

[0118] In certain embodiments, Rx is methyl or (CH2) 3-CO2H. In certain embodiments, Rx is (CH2) 3-CO2H.

[0119] In certain embodiments, the acyl donor is an anhydride or an ester. In certain embodiments, the anhydride includes but is not limited to glutaric anhydride and acetic anhydride. In certain embodiments, the ester includes, but is not limited to, vinyl acetate, isopropenyl acetate, 4-chlorophenyl acetate and ethyl methoxy acetate. In particular embodiments, the acyl donor is glutaric anhydride.

[0120] In certain embodiments, the enzyme is a lipase. In certain embodiments, the lipase includes but is not limited to Novozyme 435, CAL-A, CAL-B, PPL, PSL-C, PSL, CRL and MML. In certain embodiments, the lipase includes but is not limited to CAL-A, CAL-B, PPL, PSL-C, PSL, CRL and MML. In certain embodiments, the enzyme is CAL-B. In certain embodiments, the enzyme is Novozyme 435.

[0121] Novozyme 435 is a CAL-B lipase immobilized in a hydrophobic carrier (acrylin resin).

[0122] CAL-B is the lipase of Candida antartica B.

[0123] CAL-A is lipase from Candida antartica A.

[0124] PPL is porcine pancreas lipase.

[0125] PSL is Pseudomonas cepacia lipase.

[0126] PSL-C is an immobilized lipase from Pseudomonas cepacia.

[0127] CRL is rough Candida lipase.

[0128] MML is Mucor miehei lipase.

X scheme

[0129] Certain embodiments are directed to the synthetic multi-step method described below, namely, General Scheme X:

in which the process includes the following steps:

reacting racemic c-(which is a mixture of cc-lb and cc-la) with an acyl donor to produce racemic ee-1;

reacting racemic ee-1 (which is a mixture of e-1 and e-2) with an enzyme to produce e-2 and cc-la; and isolate cc-enantio enriched.

[0130] In certain embodiments, Rx is (Ci-C6) -Ry alkyl and Ry is selected from the group consisting of H, CN, -NRz1Rz2, C (O) Rz1, -C (O) ORz1, -C (O ) NRz1Rz2, - OC (O) NRz1Rz2, -NRz1C (O) Rz2, -NRz1C (O) NRz2, -NRz1C (O) ORz2, -SRz1, -S (O) i-2Rz1, -S (O) 2NRz1Rz2- NRz1S (O) 2Rz2, NRz1S (O) 2Rz2 and ORz1.

[0131] In certain embodiments, each Rz1 and Rz2 is independently selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 heteroalkyl, C3-10 cycloalkyl, C3.10 heterocyclyl , C6-10 heterocyclyl and 5-10 membered heteroaryl.

[0132] In certain embodiments, Rx is (C1-C6) alkyl -Ry and Ry is selected from the group consisting of H, -C (O) ORz1 and Rz1 is selected from the group consisting of H, C1-6 alkyl, C3-10 cycloalkyl and heterocyclyl of 3 to 12 members.

[0133] In certain embodiments, Rx is (C1-C6) alkyl -Ry and Ry is selected from the group consisting of H, -C (O) ORz1 and Rz1 is selected from the group consisting of H and C1-6 alkyl.

[0134] In certain embodiments, Rx is (C1-C4) alkyl -Ry and Ry is selected from the group consisting of H and CO2H.

[0135] In certain embodiments, Rx is methyl or (CH2) 3-CO2H. In certain embodiments, Rx is (CH2) 3-CO2H.

[0136] In certain embodiments, the acyl donor includes, but is not limited to, an anhydride or an acid chloride. In certain embodiments, the anhydride includes, among others, succinic anhydride and acetic anhydride. In certain embodiments, the acid chloride includes, among others, acetyl chloride and benzoyl chloride. In realizations In particular, the acyl donor is glutaric anhydride.

[0137] In certain embodiments, the enzyme is a lipase such as, among others, CAL-A, CAL-B, PPL, PSL-C, PSL, CRL and MML. In particular embodiments, the enzyme is CAL-B.

Scheme XI

[0138] Certain embodiments are directed to the synthetic multi-step method described below, namely Scheme XI:

in which the process includes the following steps:

reacting racemic c-(which is a mixture of cc-lb and cc-la) with a chiral acid to produce dd-1 and dd-2; Y

isolate dd-1 enriched with enantium.

[0139] In certain embodiments, chiral acid is selected from the group consisting of:

- individual enantiomers of carboxylic acids, including but not limited to: naproxen, phenylsuccinic acid, malic acid, 2-phenylpropionic acid, alpha-methoxyphenyl acetic acid, tartranilic acid, 3-phenylactic acid, a-hydroxyisovaleric acid, 2'-methoxy acid tartranilic, phthalic (alpha-methylbenzyl) acid, 2'-chlorotartranilic acid, pyroglutamic acid;

- individual enantiomers of derivatives of mandelic acid which include, among others: mandelic acid, 2-chloromelic acid, 4-bromo-mandelic acid, O-acetyl mandelic acid, 4-methyl-mandelic acid;

- individual enantiomers of sulfonic acids that include, among others: camphor sulfulfic acid;

- individual enantiomers of derivatives of tartaric acid, including but not limited to: tartaric acid, dibenzoyl-tartaric acid hydrate, di-p-anisoyltartaric acid, di-toluyltartaric acid, dibenzoylotartaric acid hydrate;

- individual enantiomers of phosphoric acid derivatives, which include, but are not limited to: hydrophilic phenyl, clocifos, anisiphos, BINAP phosphate; Y

- individual enantiomers of amino acids, including but not limited to the following: N-acetyl-phenylalanine, N-acetyl-leucine, N-acetyl-proline, boc-phenylalanine and boc-homophenylalanine.

[0140] In certain embodiments, chiral acid is a unique enantiomer of a carboxylic acid.

[0141] In particular embodiments, the acid is (R) -Naproxen. In particular embodiments, the acid is R- (+) - mandelic acid.

[0142] In particular embodiments, the acid is (S) -Naproxen. In particular embodiments, the acid is S - (+) - mandelic acid.

[0143] In certain embodiments, the reaction with chiral acid occurs in a solvent selected from the group consisting of water, acetonitrile, ethanol, isopropanol, ethyl methyl ketone, isopropyl acetate, dioxane, a mixture of water and organic solvents miscible with water such as ethanol and isopropanol, a halogenated solvent such as dichloromethane and chloroform. In particular embodiments, the solvent is water or isopropanol or a mixture thereof. In particular embodiments, the solvent is water. In particular embodiments, the solvent is isopropanol.

[0144] In certain embodiments, the reaction with chiral acid is stirred at 0 to 120 ° C, 20 to 120 ° C, 50 to 120 ° C, 80 to 120 ° C, or about 100 ° C. In certain embodiments, the reaction is stirred at approximately 20 ° C.

[0145] In certain embodiments, the isolation of dd-1 comprises selectively recrystallizing dd-1. In certain embodiments, recrystallization occurs in water, acetonitrile, ethanol, isopropanol, ethyl methyl ketone, acetate. of isopropyl, dioxane; a mixture of water and water-miscible organic solvents, such as ethanol and isopropanol, or a halogenated solvent, such as dichloromethane or chloroform. In certain embodiments, recrystallization occurs in a mixture of ethyl methyl ketone and water.

[0146] In certain embodiments, dd-1 is precipitated from the solution and filtered.

[0147] Schemes VII-XI describe steps and intermediates that are useful for the preparation of N-1 and / or compound of formula I.

General schemes - individual steps

[0148] Additional embodiments are directed to the individual steps of the general multistage synthetic methods described above, namely, General Schemes IV and VI through XI. These individual steps and intermediate products of the present invention are described in detail below. All substituent groups in the steps described below are those defined in the multi-step method above. A. Acylation and amidation of Meldrum acid to provide C-1:

[0149]

1. Conversion from A-1 to b-1

[0150] In particular embodiments, an equivalent of Meldrum acid (A-1) and a suitable catalyst are suspended in a suitable solvent, and the resulting solution is treated with approximately 1.2 equivalents of H-1. Approximately 2 equivalents of a suitable base are slowly added to the resulting solution, followed by the addition of approximately 1.1 equivalents of a suitable acylation reagent. The reaction occurs at approximately 20 to 80 ° C and is allowed to continue until the consumption of Meldrum acid is complete, as verified by any suitable method known in the art.

[0151] In certain embodiments, the catalyst is a compound that contains nucleophilic amines, such as, but is not limited to, 4-dimethylaminopyridine, imidazole, 1,4-diazabicyclo [2.2.2] octane, 1.8- diazabicyclo [5.4.0] undec-7-eno, or pyridine. In further embodiments, the catalyst is a compound containing nucleophilic phosphine, such as, but not limited to, triphenylphosphine. In a particular embodiment, the catalyst is 4-dimethylaminopyridine.

[0152] In certain embodiments, the solvent for the above reaction is a non-protic polar solvent or an aromatic solvent. In certain embodiments, the solvent for the above reaction is a non-protic polar solvent. In certain embodiments, the solvent for the above reaction is an aromatic solvent. Exemplary polar non-protic solvents include, but are not limited to, acetonitrile, N, N-dimethylformamide, N, N- dimethylacetamide, 1,4-dioxane or N-methyl-2-pyrrolidinone. Exemplary aromatic solvents for the above reaction include, but are not limited to, pyridine, toluene, xylene, benzene or chlorobenzene. In other additional embodiments, the solvent is a mixture comprising at least one of the above solvents. For example, in certain embodiments, the solvent is a mixture of up to three, or up to two, polar non-protic solvents selected from the group consisting of acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, 1,4-dioxane and N- methyl-2-pyrrolidinone. In other embodiments, the solvent is a mixture of up to three, or up to two, aromatic solvents selected from the group consisting of pyridine, toluene, xylene, benzene and chlorobenzene. In one embodiment, the solvent is a mixture of up to three, or up to two, solvents selected from the group consisting of acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, 1,4-dioxane, N-methyl-2- pyrrolidinone, pyridine, toluene, xylene, benzene and chlorobenzene. In a further embodiment, the solvent is acetonitrile.

[0153] In certain embodiments, R ^a is (C ¹ -C ⁴ ) alkyl, aryl (C ² -C ¹⁰ ) or aryl (C ² -C ¹⁰ ) aryl (C ¹ -C ⁴ ). In certain embodiments, R ^a is (C ¹ -C ⁴ ) alkyl, aryl (C ⁶ -C ¹⁰ ) or aryl (C ¹ -C ¹⁰ ) aryl (C ¹ -C ⁴ ). In certain embodiments, R ^a is (C ¹ -C ⁴ ) alkyl. In certain embodiments, R ^a is - CH ³ , that is, H-1 is methoxyacetic acid.

[0154] In certain embodiments, the base is an amine base, an aromatic base, inorganic carbonate, a metal hydride, an alkoxide, or mixtures thereof. In certain embodiments, the base is an amine base. In certain embodiments, the base is an aromatic base. In certain embodiments, the base is an inorganic carbonate. In certain embodiments, the base is a metal hydride. In certain embodiments, the base is an alkoxide. Exemplary amine bases include, but are not limited to, triethylamine, N, N-diisopropylethylamine, quinuclidine, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] undec-7-eno , tripropylamine, and tributylamine. Exemplary aromatic amines bases include, but are not limited to, pyridine. Exemplary inorganic carbonates include, but are not limited to, lithium carbonate, sodium carbonate, potassium carbonate or cesium carbonate. Exemplary metal hydrides include, but are not limited to, sodium hydride or potassium hydride. Examples of alkoxides include, but are not limited to, sodium methoxide, sodium tert-butoxide or lithium tert-butoxide. In other additional embodiments, the base is a mixture comprising at least one of the preceding bases. For example, in certain embodiments, the base is a mixture of up to three, or up to two, amine bases. In certain embodiments, the base is a mixture of up to three, or up to two, aromatic bases. In certain embodiments, the base is a mixture of up to three, or up to two, inorganic carbonates. In certain embodiments, the base is a mixture of up to three, or up to two, metal hydrides. In certain embodiments, the base is a mixture of up to three, or up to two, alkoxides. In certain embodiments, the base is a mixture of up to three, or up to two, bases of the group consisting of triethylamine, N, N-diisopropylethylamine, quinuclidine, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] undec-7-eno, tripropylamine, tributylamine, pyridine, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, sodium methoxide, sodium tert-butoxide and lithium tert-butoxide. In a particular embodiment, the base is triethylamine.

[0155] In certain embodiments, the acylation reagent is a carboxylic acid activating reagent, a carbodiimide derivative or a mixture thereof. In certain embodiments, the acylation reagent is a carboxylic acid activating reagent. In certain embodiments, the acylation reagent is a carbodiimide derivative. In certain embodiments, the acylation reagent is a mixture of a carboxylic acid activating reagent and a carbodiimide derivative. Exemplary carboxylic acid activating reagents include, without limitation, pivaloyl chloride, carbonyldiimidazole, thionyl chloride and oxalyl chloride. Exemplary carbodiimide derivatives include, without limitation, carbonyldiimidazole and N, N'-dicyclohexylcarbodiimide. In certain embodiments, the acylation reagent is pivaloyl chloride, carbonyldiimidazole, thionyl chloride, oxalyl chloride or N, N'- dicyclohexylcarbodiimide. In certain embodiments, the acylation reagent is a mixture of up to three, or up to two, reagents of the groups consisting of pivaloyl chloride, carbonyldiimidazole, thionyl chloride, oxalyl chloride or NN'-dicyclohexylcarbodiimide. In certain embodiments, the acylation reagent is pivaloyl chloride. In certain embodiments, the reaction occurs at about 20 to 70 ° C, about 20 to 60 ° C, about 20 to 50 ° C, about 20 to 40 ° C, about 20 to 30 ° C, about 30 to 80 ° C, approximately 30 to 70 ° C, approximately 30 to 60 ° C, approximately 30 to 50 ° C, approximately 30 to 40 ° C, approximately 40 to 80 ° C, approximately 40 to 70 ° C, approximately 40 to 60 ° C, approximately 40 to 50 ° C, approximately 50 to 80 ° C, approximately 50 to 70 ° C, approximately 50 to 60 ° C, approximately 60 to 80 ° C, approximately 60 to 70 ° C, approximately 70 to 80 ° C, or any subinterval between them. In particular embodiments, the reaction occurs at about 35 to 40 ° C, about 40 to 45 ° C, about 45 to 50 ° C, or any sub-interval between them.

[0156] In particular embodiments, the catalyst is 4-dimethylaminopyridine, the solvent is acetonitrile, Ra is -CH3, the base is triethylamine, the acylation reagent is pivaloyl chloride and the reaction occurs at about 45 to 50 ° C.

2. Conversion from b-1 to C-1

[0157] In a separate vessel, approximately 1.2 equivalents of J-1 are suspended in a suitable solvent. The resulting solution is treated with approximately 1.5 equivalents of a suitable acid, and then this acid solution is added to the previous acylation reaction in progress. The reaction is allowed to continue for about 12 to about 24 hours at about 20 to 80 ° C, after which the solvent is removed and C-1 is recovered and purified from the residue using any suitable technique known in the art, such as , but not limited to solvent extraction, silica gel chromatography and crystallization.

[0158] In certain embodiments, J-1 is suspended in a non-protic polar solvent or an aromatic solvent. In certain embodiments, J-1 is suspended in a non-protic polar solvent. In certain embodiments, J-1 is suspended in an aromatic solvent. Exemplary polar non-protic solvents include, but are not limited to, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, 1,4-dioxane and N-methyl-2-pyrrolidinone. Exemplary aromatic solvents include, but are not limited to, pyridine, toluene, xylene, benzene and chlorobenzene. In other additional embodiments, J-1 is suspended in a solvent mixture comprising one or more non-protic polar solvents and / or one or more aromatic solvents. In certain embodiments, J-1 is suspended in a solvent mixture comprising up to three, or up to two, polar non-protic solvents. In certain embodiments, J-1 is suspended in a solvent mixture comprising up to three, or up to two aromatic solvents. In certain embodiments, J-1 is suspended in a solvent mixture comprising up to three, or up to two, solvents of the group consisting of acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, 1,4-dioxane, N -methyl-2-pyrrolidinone, pyridine, toluene, xylene, benzene and chlorobenzene. In a further embodiment, J-1 is suspended in acetonitrile.

[0159] In particular embodiments, the acid is an inorganic acid, an organic acid or a halogenated organic acid. In certain embodiments, the acid is an inorganic acid. In certain embodiments, the acid is an organic acid. Examples of inorganic acids include, among others, hydrochloric acid, hydrobromic acid and hydroiodic acid. Examples of organic acids include, among others, formic acid and acetic acid. In yet other embodiments, the organic acid is a halogenated organic acid. Examples of halogenated organic acids include, but are not limited to, trifluoromethanesulfonic acid, trifluoroacetic acid, trichloroacetic acid and perfluoropropionic acid. In other additional embodiments, the acid is a mixture comprising one or more organic acids and one or more inorganic acids. In certain embodiments, the acid is a mixture comprising up to three, or up to two, organic acids. In certain embodiments, the acid is a mixture comprising up to three, or up to two, halogenated organic acids. In certain embodiments, the acid is a mixture comprising up to three, or up to two, inorganic acids. In a certain embodiment, the acid is a mixture of up to three, or up to two acids selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, formic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, trichloroacetic acid and perfluoropropionic acid. In a particular embodiment, the acid is trifluoroacetic acid.

[0160] In particular embodiments, each Hal is independently -F or -Cl. In a particular embodiment, Hal is -F In certain embodiments, n = 1-3. In certain embodiments, n = 2. In certain embodiments, n = 3. In other embodiments, J-1 is

In certain embodiments, J-1 is

In additional embodiments, J-1 is

[0161] In other additional embodiments, J-1 is in the form of a salt or co-crystal, such as, but not limited to, a salt or co-crystal of hydrochloric acid or trifluoroacetic acid. In certain embodiments, J-1 is a salt or co-crystal of methanesulfonic acid.

[0162] For example, in certain embodiments, J-1 is:

[0163] In a particular embodiment, J-1 is

[0164] In a particular embodiment, J-1 is

[0165] For example, in certain embodiments, J-1 is:

[0166] In a particular embodiment, J-1 is

[0167] In a particular embodiment, J-1 is

[0168] In certain embodiments, the reaction occurs at about 20 to 70 ° C, about 20 to 60 ° C, about 20 to 50 ° C, about 20 to 40 ° C, about 20 to 30 ° C, about 30 to 80 ° C, approximately 30 to 70 ° C, approximately 30 to 60 ° C, approximately 30 to 50 ° C, approximately 30 to 40 ° C, approximately 40 to 80 ° C, approximately 40 to 70 ° C, approximately 40 to 60 ° C, approximately 40 to 50 ° C, approximately 50 to 80 ° C, approximately 50 to 70 ° C, approximately 50 to 60 ° C, approximately 60 to 80 ° C, approximately 60 to 70 ° C, approximately 70 to 80 ° C, or any subinterval between them. In particular embodiments, the reaction occurs at about 35 to 40 ° C, about 40 to 45 ° C, about 45 to 50 ° C, or any sub-interval between them.

[0169] In certain embodiments, the solvent is removed under reduced pressure. In particular embodiments, C-1 is extracted from the crude residue by solvent extraction. In a particular embodiment, the crude residue is dissolved in an organic solvent, such as ethyl acetate, and the organic layer is washed with water. The combined aqueous layers are extracted with an organic solvent, such as ethyl acetate. The combined organic layers are wash with a saturated solution of sodium bicarbonate and the combined bicarbonate washes are again extracted with an organic solvent such as ethyl acetate. The total combined organic layers are dried over a drying agent, such as magnesium sulfate, filtered and concentrated under reduced pressure. The resulting crude material is purified using any suitable technique, such as silica gel chromatography to obtain C-1.

[0170] In particular embodiments, J-1 is suspended in acetonitrile, the acid is trifluoroacetic acid, J-1 is

and the reaction occurs at approximately 45 to 50 ° C.

3. Formation of C-1 through salt b-1 * J-1

[0171] Alternatively, in certain embodiments, C-1 is formed through the formation of a b-1J-1 salt following the following procedure.

to. Salt formation b-1J-1 by adding J-1 to b-1

[0172]

[0173] B-1 free acid (approximately 1 equivalent) is dissolved in a solvent, followed by the addition of J-1 (approximately 1 to approximately 5 equivalents). In certain embodiments, the salt is aged up to 12 hours, up to 10 hours, up to 8 hours, up to 6 hours, up to 4 hours or up to 3 hours. The salt is obtained by any suitable method known in the art, which includes, among others, solvent filtration, extraction, crystallization and silica gel chromatography.

[0174] In certain embodiments, the solvent for the above reaction is a non-protic polar solvent or an aromatic solvent. In certain embodiments, the solvent for the above reaction is a non-protic polar solvent. In certain embodiments, the solvent for the above reaction is an aromatic solvent. Exemplary polar non-protic solvents include, but are not limited to, acetonitrile, N, N-dimethylformamide, N, N- dimethylacetamide, 1,4-dioxane or N-methyl-2-pyrrolidinone. Exemplary aromatic solvents for the above reaction include, but are not limited to, pyridine, toluene, xylene, benzene or chlorobenzene. In other additional embodiments, the solvent is a mixture comprising at least one of the above solvents. For example, in certain embodiments, the solvent is a mixture of up to three, or up to two, polar non-protic solvents selected from the group consisting of acetonitrile, N, N-dimethylformamide, NN-dimethylacetamide, 1,4-dioxane and n- methyl-2-pyrrolidinone. In other embodiments, the solvent is a mixture of up to three, or up to two, aromatic solvents selected from the group consisting of pyridine, toluene, xylene, benzene and chlorobenzene. In one embodiment, the solvent is a mixture of up to three, or up to two, solvents selected from the group consisting of acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, 1,4-dioxane, N-methyl-2- pyrrolidinone, pyridine, toluene, xylene, benzene and chlorobenzene. In a further embodiment, the solvent is acetonitrile.

[0175] In some embodiments, b-1.J-1 is:

[0176] In certain embodiments, the reaction is stirred at about 15 to 30 ° C, about 20 to 70 ° C, about 20 to 60 ° C, about 20 to 50 ° C, about 20 to 40 ° C, about 20 to 30 ° C, approximately 30 to 80 ° C, approximately 30 to 70 ° C, approximately 30 to 60 ° C, approximately 30 to 50 ° C, approximately 30 to 40 ° C, approximately 40 to 80 ° C, approximately 40 to 70 ° C, approximately 40 to 60 ° C, approximately 40 to 50 ° C, approximately 50 to 80 ° C, approximately 50 to 70 ° C, approximately 50 to 60 ° C, approximately 60 to 80 ° C, approximately 60 to 70 ° C, approximately 70 to 80 ° C, or any subinterval between them. In further embodiments, the reaction proceeds from about 15 to about 25 ° C.

[0177] In certain embodiments, the solvent is acetonitrile and the reaction proceeds from about 18 to about 25 ° C. second.

b. Formation of C-1 from salt b-1 * J-1

[0178]

[0179] Salt b-1J-1 (approximately 1 equivalent) is suspended in a suitable solvent. The resulting solution is treated with approximately 0.1 to 1 equivalents of a suitable acid. The reaction is allowed to continue for about 12 to about 24 hours at about 20 to 80 ° C, after which the solvent is removed and C-1 is recovered and purified from the residue using any suitable technique known in the art, such as , but not limited to solvent extraction, silica gel chromatography, crystallization and filtration.

[0180] In certain embodiments, the solvent for the above reaction is a non-protic polar solvent or an aromatic solvent. In certain embodiments, the solvent for the above reaction is a non-protic polar solvent. In certain embodiments, the solvent for the above reaction is an aromatic solvent. Exemplary polar non-protic solvents include, but are not limited to, acetonitrile, N, N-dimethylformamide, N, N- dimethylacetamide, 1,4-dioxane or N-methyl-2-pyrrolidinone. Exemplary aromatic solvents for the above reaction include, but are not limited to, pyridine, toluene, xylene, benzene or chlorobenzene. In other additional embodiments, the solvent is a mixture comprising at least one of the above solvents. For example, in certain embodiments, the solvent is a mixture of up to three, or up to two, polar non-protic solvents selected from the group consisting of acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, 1,4-dioxane and N- methyl-2-pyrrolidinone. In other embodiments, the solvent is a mixture of up to three, or up to two, aromatic solvents selected from the group consisting of pyridine, toluene, xylene, benzene and chlorobenzene. In one embodiment, the solvent is a mixture of up to three, or up to two, solvents selected from the group consisting of acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, 1,4-dioxane, N-methyl-2- pyrrolidinone, pyridine, toluene, xylene, benzene and chlorobenzene. In a further embodiment, the solvent is acetonitrile.

[0181] In particular embodiments, the acid is an inorganic acid, an organic acid or a halogenated organic acid. In certain embodiments, the acid is an inorganic acid. In certain embodiments, the acid is an organic acid. Examples of inorganic acids include, among others, hydrochloric acid, hydrobromic acid and hydroiodic acid. Examples of organic acids include, among others, formic acid and acetic acid. In yet other embodiments, the organic acid is a halogenated organic acid. Examples of halogenated organic acids include, but are not limited to, trifluoromethanesulfonic acid, trifluoroacetic acid, trichloroacetic acid and perfluoropropionic acid. In certain embodiments, the acid is trifluoroacetic acid. In other embodiments In addition, the acid is a mixture comprising one or more organic acids and one or more inorganic acids. In certain embodiments, the acid is a mixture comprising up to three, or up to two, organic acids. In certain embodiments, the acid is a mixture comprising up to three, or up to two, halogenated organic acids. In certain embodiments, the acid is a mixture comprising up to three, or up to two, inorganic acids. In a certain embodiment, the acid is a mixture of up to three, or up to two acids selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, formic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, trichloroacetic acid and perfluoropropionic acid. In a particular embodiment, the acid is trifluoroacetic acid.

[0182] In certain embodiments, upon completion of the addition, the reaction is heated to about 20 to 70 ° C, about 20 to 60 ° C, about 20 to 50 ° C, about 20 to 40 ° C, about 20 to 30 ° C, approximately 30 to 80 ° C, approximately 30 to 70 ° C, approximately 30 to 60 ° C, approximately 30 to 50 ° C, approximately 30 to 40 ° C, approximately 40 to 80 ° C, approximately 40 to 70 ° C, approximately 40 to 60 ° C, approximately 40 to 50 ° C, approximately 50 to 80 ° C, approximately 50 to 70 ° C, approximately 50 to 60 ° C, approximately 60 to 80 ° C, approximately 60 to 70 ° C , around 70 to 80 ° C, or any subinterval between them. In further embodiments, the reaction proceeds at approximately 60 ° C.

[0183] In particular embodiments, the solvent is acetonitrile, the acid is trifluoroacetic acid and the reaction proceeds at approximately 60 ° C.

B. Alkylation of C-1 to form E-1:

[0184]

[0185] A solution of approximately one equivalent of C-1 in a suitable solvent is treated with approximately one to one and a half equivalents of an alkylated formamide acetal and stirred at approximately 0 to 60 ° C for approximately 10 hours to approximately 18 hours The reaction is treated with approximately one equivalent of K-1 and allowed to continue for approximately one to approximately four hours, and then stopped by the addition of an acid. E-1 is then extracted and purified by any suitable method known in the art, which includes, among others, solvent extraction, crystallization and silica gel chromatography.

[0186] In a particular embodiment, the solvent is a non-protic polar organic solvent such as, but not limited to, 2-methyl tetrahydrofuran, tetrahydrofuran, acetonitrile, diisopropyl ether, methyl tert-butyl ether, N, N- dimethylformamide, N , N-dimethylacetamide, 1,4-dioxane, N-methyl-2-pyrrolidinone, or mixtures thereof. In a further embodiment, the solvent is 2-methyl tetrahydrofuran.

[0187] In certain embodiments, the alkylated formamide acetal is selected from the group consisting of N, N- dimethylformamide acetyl dimethyl, N, N-dimethylformamide diethyl acetal, N, N-dimethylformamide diisopropylacetal, N, N- diethylformamide dimethyl acetal, and N, N -diisopropylformamide dimethyl acetal. In a particular embodiment, the alkylated formamide acetal is N, N-dimethylformamide dimethyl acetal.

[0188] In particular embodiments, an equivalent of C-1 is treated with approximately 1.1 equivalents of the alkylated formamide acetal.

[0189] In certain embodiments, R ¹ is (C ¹ -C ⁴ ) alkyl, aryl (C ² -C ¹⁰ ) or aryl (C ² -C ¹⁰ ) aryl (C ¹ -C ⁴ ). In certain embodiments, R ¹ is (C ¹ -C ⁴ ) alkyl, aryl (C ⁶ -C ¹⁰ ) or aryl (C ¹ -C ¹⁰ ) aryl (C ¹ -C ⁴ ). In certain embodiments, R ¹ is C ¹ -C ⁴ alkyl. In other embodiments, R ¹ is - CH ³ , that is, K-1 is amino acetaldehyde dimethyl acetal.

[0190] In certain embodiments, the reaction is interrupted with an inorganic acid, an organic acid or a halogenated organic acid. In certain embodiments, the acid is an inorganic acid. In certain embodiments, the acid is an organic acid. In certain embodiments, the acid is a halogenated organic acid. Examples of inorganic acids include, among others, hydrochloric acid, hydrobromic acid and hydroiodic acid. Examples of organic acids include, among others, formic acid and acetic acid. Examples of halogenated organic acids include, but are not limited to, trifluoromethanesulfonic acid, trifluoroacetic acid, trichloroacetic acid and perfluoropropionic acid. In other additional embodiments, the acid is a mixture comprising one or more organic acids, one or more inorganic acids and / or one or more halogenated organic acids. In certain embodiments, the acid is a mixture comprising up to three, or up to two, organic acids. In certain embodiments, the acid is a mixture comprising up to three, or up to two, halogenated organic acids. In certain embodiments, the acid is a mixture comprising up to three, or up to two, inorganic acids. In a certain embodiment, the acid is a mixture of up to three, or up to two acids selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, formic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, trichloroacetic acid and perfluoropropionic acid. In a particular embodiment, the acid is trifluoroacetic acid. In particular embodiments, the reaction is interrupted with hydrochloric acid. In particular embodiments, the reaction is interrupted with 2N HCl. In certain embodiments, the reaction does not turn off.

[0191] In certain embodiments, the reaction proceeds at about 10 to 60 ° C, about 10 to 50 ° C, about 10 to 40 ° C, about 10 to 30 ° C, about 10 to 20 ° C, 20 to 60 ° C, approximately 20 to 50 ° C, approximately 20 to 40 ° C, approximately 20 to 30 ° C, approximately 30 to 60 ° C, approximately 30 to 50 ° C, approximately 30 to 40 ° C, approximately 40 to 60 ° C , approximately 40 to 50 ° C, approximately 50 to 60 ° C, or any subinterval between them. In particular embodiments, the reaction proceeds at room temperature. In further embodiments, the reaction proceeds from about 15 to about 25 ° C.

[0192] In particular embodiments, the solvent is 2-methyl tetrahydrofuran, the alkylated formamide acetal is W, W-dimethylformamide dimethylacetal, R ¹ is -CH ³ , and the reaction proceeds from about 18 to about 23 ° C.

C. Cyclization of E-1 to form F-1:

[0193]

[0194] In particular embodiments, a solution of approximately one equivalent of E-1 and approximately one to five equivalents of M-1 in a suitable first solvent is combined and cooled to approximately 0 to 5 ° C. In certain embodiments, the base is slowly introduced into the reaction mixture, while the internal reaction temperature is kept cold throughout the addition (e.g., below room temperature, or below about 25 ° C, or below about 20 ° C, or below about 15 ° C). Once the addition is complete, the reaction is heated at about 20 to 80 ° C for at least about 14 hours.

[0195] After this time, the reaction can be diluted with an aqueous acid solution and an additional suitable organic solvent and the product extracted and purified by any suitable method known in the art, including, but not limited to, solvent extraction, crystallization, and silica gel chromatography. In certain embodiments, the aqueous acid solution is hydrochloric acid and acetic acid. For example, in certain embodiments, the aqueous acid solution is glacial acetic acid.

[0196] In particular embodiments, the first solvent is one or more alcohols, one or more polar organic solvents, or a mixture of or more alcohols and one or more polar organic solvents. In certain embodiments, the first solvent is up to three alcohols, up to three polar organic solvents, or a mixture thereof (i.e., a mixture of up to three, or up to two, alcohols and up to three, or up to two, polar organic solvents ). In certain embodiments, the first solvent is one or two alcohols, one or two polar organic solvents, or a mixture thereof (ie, a mixture of one or two alcohols and one or two polar organic solvents). In certain embodiments, the first solvent is an alcohol. In certain embodiments, the first solvent is a polar organic solvent. Exemplary alcohols include, but are not limited to, methanol, ethanol, W-propanol, 2-propanol, butanol and tert-butanol. Exemplary polar organic solvents include, but are not limited to, acetone, acetonitrile, W, A / -dimethylformamide, W, A / -dimethylacetamide, 1,4-dioxane and n-methyl-2-pyrrolidinone. In certain embodiments, the first solvent is methanol, ethanol, A / -propanol, 2-propanol, butanol, tert-butanol acetone, acetonitrile, W, A / -dimethylformamide, W, A / -dimethylacetamide, 1,4-dioxane or n- methyl-2-pyrrolidinone. In a certain embodiment, the first solvent is methanol.

[0197] In particular embodiments, the base is a metal hydride, an alkoxide or a bis (trialkylsilyl) amide. In certain embodiments, the base is a metal hydride. In certain embodiments, the base is an alkoxide. In certain embodiments, the base is a bis (trialkylsilyl) amide. Exemplary metal hydrides include, but are not limited to lithium hydride, sodium hydride and potassium hydride. Examples of alkoxides include, but are not limited to, sodium methoxide, sodium tert-butoxide, sodium ethoxide, potassium tert-butoxide, potassium ethoxide, sodium tert - pentoxide and potassium tert-butoxide. Exemplary bis (trialkylsilyl) amide bases include, but are not limited to, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide and potassium bis (trimethylsilyl) amide. In other additional embodiments, the base is a mixture of at least one of the above bases. In certain embodiments, the base is a mixture of up to three, or up to two, metal hydrides. In certain embodiments, the base is a mixture of up to three, or up to two, alkoxides. In certain embodiments, the base is a mixture of up to three, or up to two, metal bis (trialkylsilyl) amides. In certain embodiments, the base is a mixture of up to three or up to two of the following bases: lithium hydride, sodium hydride, potassium hydride, sodium methoxide, sodium tert-butoxide, sodium ethoxide, tert-butoxide potassium, potassium ethoxide, sodium tert-pentoxide, lithium tert-butoxide, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide or potassium bis (trimethylsilyl) amide. In particular embodiments, the base is sodium methoxide.

[0198] In certain embodiments, R2 is (C1-C4) alkyl, (C2-C10) aryl or (C1-C10) aryl (C1-C4) aryl. In certain embodiments, R2 is (C1-C4) alkyl, (C6-C10) aryl, or (C1-C10) aryl (C1-C4) aryl. In certain embodiments, R2 is C1-C4 alkyl. In certain embodiments, R2 is -CH3.

[0199] In certain embodiments, after the addition is complete, the reaction is heated to about 20 to 70 ° C, about 20 to 60 ° C, about 20 to 50 ° C, about 20 to 40 ° C, about 20 at 30 ° C, about 30 to 80 ° C, about 30 to 70 ° C, about 30 to 60 ° C, about 30 to 50 ° C, about 30 to 40 ° C, about 40 to 80 ° C, about 40 to 70 ° C, approximately 40 to 60 ° C, approximately 40 to 50 ° C, approximately 50 to 80 ° C, approximately 50 to 70 ° C, approximately 50 to 60 ° C, approximately 60 to 80 ° C, approximately 60 to 70 ° C, around 70 to 80 ° C, or any subinterval between them.

[0200] In particular embodiments, the first solvent is an alcohol, the base is an alkoxide, once the addition is complete, the reaction is heated to about 40 to about 50 ° C and R2 is (C1-C4) alkyl.

[0201] In particular embodiments, the first solvent is methanol, the base is sodium methoxide, once the addition is complete, the reaction is heated to about 40 to about 50 ° C and R2 is -CH3.

D. Alkylation and cyclization of C-1 to form F-1:

[0202]

[0203] In certain embodiments, about one equivalent of C-1 and about 1 to about 5 equivalents of an alkylated mamide acetal are combined in a reaction vessel, and the reaction mixture is stirred for approximately 30 minutes. In certain embodiments, about one equivalent of C-1 and about 1 to about 3 equivalents of an alkylated formamide acetal are combined in a reaction vessel. A suitable first solvent and approximately one equivalent of K-1 are added to the mixture, and the reaction is allowed to continue for several hours, after which the first solvent is removed by any suitable means known in the art.

[0204] The resulting material is dissolved in a suitable second solvent and about 1 to about 5 equivalents of M-1 are added. The reaction mixture is cooled to about 0 ° C to about 5 ° C, and then about one and a half to two equivalents of a base are slowly added from the reaction mixture. The internal temperature of the reaction is kept cold throughout the addition (e.g., below room temperature or below about 25 ° C, or below about 20 ° C, or below about 15 ° C). Once the addition is complete, the reaction is heated at about 20 to 80 ° C for about 8 to about 16 hours.

[0205] After this time has elapsed, the reaction is cooled to room temperature, stopped by the addition of an acid and diluted with the addition of an organic solvent. The product, F-1, can then be extracted and purified by any suitable method known in the art, which includes, among others, solvent extraction, crystallization and silica gel chromatography.

[0206] In certain embodiments, R ^a is (C ¹ -C ⁴ ) alkyl, aryl (C ² -C ¹⁰ ) or aryl (C ¹ -C ¹⁰ ) aryl (C ¹ -C ⁴ ). In certain embodiments, R ^a is (C ¹ -C ⁴ ) alkyl, aryl (C ⁶ -C ¹⁰ ) or aryl (C ¹ -C ¹⁰ ) aryl (C ¹ -C ⁴ ). In certain embodiments, R ^a is C ¹ -C ⁴ alkyl. In certain embodiments, R ^a is -CH ³ .

[0207] In a particular embodiment, the first solvent is a non-protic polar organic solvent such as, but not limited to, 2-methyl tetrahydrofuran, tetrahydrofuran, acetonitrile, diisopropyl ether, methyl tere-butyl ether, N, N- dimethylformamide. , N, N-dimethylacetamide, 1,4-dioxane, N-methyl-2-pyrrolidinone, or mixtures thereof. In a further embodiment, the first solvent is 2-methyl tetrahydrofuran.

[0208] In certain embodiments, the alkylated formamide acetal is selected from the group consisting of N, N- dimethylformamide acetyl dimethyl, N, N-dimethylformamide diethyl acetal, N, N-dimethylformamide diisopropylacetal, N, N- diethylformamide dimethyl acetal, and N, N -diisopropylformamide dimethyl acetal. In a particular embodiment, the alkylated formamide acetal is N, N-dimethylformamide dimethyl acetal.

[0209] In certain embodiments, R ¹ is (C ¹ -C ⁴ ) alkyl, aryl (C ² -C ¹⁰ ) or aryl (C ² -C ¹⁰ ) aryl (C ¹ -C ⁴ ). In certain embodiments, R ¹ is (C ¹ -C ⁴ ) alkyl, aryl (C ⁶ -C ¹⁰ ) or aryl (C ¹ -C ¹⁰ ) aryl (C ¹ -C ⁴ ). In certain embodiments, R ¹ is C ¹ -C ⁴ alkyl. In other embodiments, R ¹ is - CH ³ , that is, K-1 is amino acetaldehyde dimethyl acetal.

[0210] In particular embodiments, the base is a metal hydride, a bis (trialkylsilyl) amide base, or an alkoxide. In certain embodiments, the base is a metal hydride. In particular embodiments, the base is a bis (trialkylsilyl) amide base. In particular embodiments, the base is an alkoxide. Exemplary metal hydrides include, but are not limited to lithium hydride, sodium hydride and potassium hydride. Exemplary bis (trialkylsilyl) amide bases include, but are not limited to, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide and potassium bis (trimethylsilyl) amide. Examples of alkoxides include, among others, sodium methoxide, sodium tere-butoxide, sodium ethoxide, potassium tere-butoxide, potassium ethoxide, sodium tere-pentoxide and lithium tere-butoxide. In other additional embodiments, the base is a mixture of at least one of the above bases. In certain embodiments, the base is a mixture of up to three, or up to two, metal hydrides. In certain embodiments, the base is a mixture of up to three, or up to two, bis (trialkylsilyl) amide base. In certain embodiments, the base is a mixture of up to three, or up to two, alkoxides. In certain embodiments, the base is a mixture of up to three, or up to two bases selected from the group consisting of lithium hydride, sodium hydride, potassium hydride, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide , potassium bis (trimethylsilyl) amide, sodium methoxide, sodium tere-butoxide, sodium ethoxide, potassium tere-butoxide, potassium ethoxide, sodium tere-pentoxide and lithium tere-butoxide. In particular embodiments, the base is sodium methoxide. In particular embodiments, an alcohol-based solution is added to the reaction. A suitable alcohol includes, but is not limited to, methanol, ethanol, n-propanol, 2-propanol, butanol or tere-butanol. In a certain embodiment, the base is sodium methoxide. In a certain embodiment, the base is added as a 30% solution of sodium methoxide in methanol.

[0211] In particular embodiments, the second solvent is an alcohol or a polar solvent. In certain embodiments, the second solvent is an alcohol. In certain embodiments, the second solvent is a polar solvent. Exemplary alcohols include, but are not limited to, methanol, ethanol, n-propanol, 2-propanol, butanol and tere-butanol. Exemplary polar organic solvents include, but are not limited to, acetone, acetonitrile, N, N- dimethylformamide, N, N-dimethylacetamide, 1,4-dioxane or n-methyl-2-pyrrolidinone. In a certain embodiment, the second solvent is methanol.

[0212] In certain embodiments, R ² is (C ¹ -C ⁴ ) alkyl, aryl (C ² -C ¹⁰ ) or aryl (C ² -C ¹⁰ ) (C ¹ -C ⁴ ) alkyl. In certain embodiments, R ² is (C ¹ -C ⁴ ) alkyl, aryl (C ⁶ -C ¹⁰ ), or aryl (C ¹ -C ¹⁰ ) aryl (C ¹ -C ⁴ ). In certain embodiments, R ² is C ¹ -C ⁴ alkyl. In certain embodiments, R ² is -CH ³ .

[0213] In certain embodiments, upon completion of the addition, the reaction is heated to about 20 to 70 ° C, about 20 to 60 ° C, about 20 to 50 ° C, about 20 to 40 ° C, about 20 to 30 ° C, approximately 30 to 80 ° C, approximately 30 to 70 ° C, approximately 30 to 60 ° C, approximately 30 to 50 ° C, approximately 30 to 40 ° C, approximately 40 to 80 ° C, approximately 40 to 70 ° C, approximately 40 to 60 ° C, approximately 40 to 50 ° C, approximately 50 to 80 ° C, approximately 50 to 70 ° C, approximately 50 to 60 ° C, approximately 60 to 80 ° C, approximately 60 to 70 ° C , approximately 70 to 80 ° C, or any subinterval between them.

[0214] In particular embodiments, R ^a is (C ¹ -C ⁴ ) alkyl, the first solvent is 2-methyl tetrahydrofuran, acetal of alkylated formamide is N, N-dimethylformamide dimethylacetal, R ¹ is alkyl (C ¹ -C ⁴ ), the base is an alkoxide, the second solvent is an alcohol, once the addition is complete, the reaction is heated to approximately 40 at about 50 ° C, and R ² is (C ¹ -C ⁴ ) alkyl.

[0215] In particular embodiments, R ^a is -CH ³ , the first solvent is 2-methyl tetrahydrofuran, the alkylated formamide acetal is N, N-dimethylformamide dimethylacetal, R ¹ is -CH ³ , the base is sodium methoxide, The second solvent is methanol. After the addition is complete, the reaction is heated to about 40 to about 50 ° C, and R ² is -CH ³ .

E. Preparation of EE-1 from D-1

[0216]

[0217] D-1 is reacted with M-1 to give EE-1. For example. D-1 is dissolved in a suitable solvent and 1 to about 5 equivalents of M-1 are added. The reaction mixture is cooled to about 0 ° C to about 5 ° C, and then about one and a half to two equivalents of a base are slowly added from the reaction mixture. The internal temperature of the reaction is kept cold throughout the addition (e.g., below room temperature or below about 25 ° C, or below about 20 ° C, or below about 15 ° C). Once the addition is complete, the reaction is heated at about 20 to 80 ° C for about 8 to about 16 hours.

[0218] After this time has elapsed, the reaction is cooled to room temperature, stopped by the addition of an acid and diluted with the addition of an organic solvent. The product, EE-1, can then be extracted and purified by any suitable method known in the art, which includes, among others, solvent extraction, crystallization and silica gel chromatography.

[0219] In certain embodiments, R ^a is (C ¹ -C ⁴ ) alkyl, aryl (C ² -C ¹⁰ ) or aryl (C ¹ -C ¹⁰ ) aryl (C ¹ -C ⁴ ). In certain embodiments, R ^a is (C ¹ -C ⁴ ) alkyl, aryl (C ⁶ -C ¹⁰ ) or aryl (C ¹ -C ¹⁰ ) aryl (C ¹ -C ⁴ ). In certain embodiments, R ^a is C ¹ -C ⁴ alkyl. In particular embodiments, R ^a is -CH ³ .

[0220] In certain embodiments, R ^b is (C ¹ -C ⁴ ) alkyl, aryl (C ² -C ¹⁰ ) or aryl (C ² -C ¹⁰ ) aryl (C ¹ -C ⁴ ). In certain embodiments, in certain embodiments, each R ^b is, independently (C ¹ -C ⁴ ) alkyl, aryl (C ⁶ -C ¹⁰ ) or aryl (C ⁶ -C ¹⁰ ) (C ¹ -C ⁴ ). In certain embodiments, R ^b is C ¹ -C ⁴ alkyl. In additional embodiments, R ^b is -CH ³ . In certain embodiments, in certain embodiments, each R ^b is -CH ³ .

[0221] In particular embodiments, the base is an inorganic carbonate, a metal hydride, or an alkoxide, or a mixture thereof. In particular embodiments, the base is an inorganic carbonate. In particular embodiments, the base is a metal hydride. In particular embodiments, the base is an alkoxide. Exemplary inorganic carbonates include, without limitation, lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate. Exemplary metal hydrides include, without limitation, sodium hydride and potassium hydride. Examples of alkoxides include, without limitation, sodium methoxide, sodium tert-butoxide, sodium ethoxide, potassium tert-butoxide, potassium ethoxide, sodium ferc-pentoxide and lithium ferc-butoxide. In certain embodiments, the base is a mixture of up to three, or in other embodiments, up to two, inorganic carbonates. In certain embodiments, the base is a mixture of up to three, or in other embodiments, up to two, metal hydrides. In certain embodiments, the base is a mixture of up to three, or in other embodiments, up to two, alkoxides. In certain embodiments, the base is a mixture of up to three, or in other embodiments, up to two, bases selected from the group consisting of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, hydride. potassium, sodium FERC-butoxide, sodium ethoxide, potassium butoxide FERC, potassium ethoxide, sodium penóxido ferc- FERC-butoxide. In particular embodiments, the base is sodium methoxide.

[0222] In particular embodiments, the solvent is an alcohol or a polar solvent. In certain embodiments, the solvent is an alcohol. In certain embodiments, the solvent is a polar solvent. Exemplary alcohols include, but are not limited to, methanol, ethanol, n-propanol, 2-propanol, butanol and ferc-butanol. Exemplary polar organic solvents include, but are not limited to, acetone, acetonitrile, N, N-dimethylformamide, N, N- dimethylacetamide, 1,4-dioxane or W-methyl-2-pyrrolidinone. In a certain embodiment, the solvent is W-methyl-2-pyrrolidinone.

[0223] In certain embodiments, the reaction is interrupted with an inorganic acid, an organic acid or a halogenated organic acid. In certain embodiments, the acid is an inorganic acid. In certain embodiments, the acid is an organic acid. In certain embodiments, the acid is a halogenated organic acid. Examples of inorganic acids include, among others, hydrochloric acid, hydrobromic acid and hydroiodic acid. Examples of organic acids include, among others, formic acid and acetic acid. Examples of halogenated organic acids include, but are not limited to, trifluoromethanesulfonic acid, trifluoroacetic acid, trichloroacetic acid and perfluoropropionic acid. In other additional embodiments, the acid is a mixture comprising one or more organic acids, one or more inorganic acids and / or one or more halogenated organic acids. In certain embodiments, the acid is a mixture comprising up to three, or up to two, organic acids. In certain embodiments, the acid is a mixture comprising up to three, or up to two, halogenated organic acids. In certain embodiments, the acid is a mixture comprising up to three, or up to two, inorganic acids. In a certain embodiment, the acid is a mixture of up to three or up to two acids selected from the group consisting of hydrochloric acid, hydrobromic acid, iohydric acid, formic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, trichloroacetic acid and perfluoropropionic acid. In a particular embodiment, the acid is trifluoroacetic acid. In particular embodiments, the reaction is interrupted with hydrochloric acid. In particular embodiments, the reaction is interrupted with 2 N HCl. In certain embodiments, the reaction does not turn off.

[0224] In certain embodiments, R ² is (C ¹ -C ⁴ ) alkyl, aryl (C ² -C ¹⁰ ) or aryl (C ² -C ¹⁰ ) (C ¹ -C ⁴ ) alkyl. In certain embodiments, R ² is (C ¹ -C ⁴ ) alkyl, aryl (C ⁶ -C ¹⁰ ), or aryl (C ¹ -C ¹⁰ ) aryl (C ¹ -C ⁴ ). In certain embodiments, R ² is C ¹ -C ⁴ alkyl. In certain embodiments, R ² is -CH ³ .

[0225] In certain embodiments, upon completion of the addition, the reaction is heated to about 20 to 80 ° C, about 20 to 80 ° C, about 20 to 60 ° C, about 20 to 50 ° C, about 20 to 40 ° C, approximately 20 to 30 ° C, approximately 30 to 80 ° C, approximately 30 to 70 ° C, approximately 30 to 60 ° C, approximately 30 to 50 ° C, approximately 30 to 40 ° C, approximately 40 to 80 ° C, approximately 40 to 70 ° C, approximately 40 to 60 ° C, approximately 40 to 50 ° C, approximately 50 to 80 ° C, approximately 50 to 70 ° C, approximately 50 to 60 ° C, approximately 60 to 80 ° C , approximately 60 to 70 ° C, approximately 70 to 80 ° C, or any subinterval between them.

[0226] In particular embodiments, R ² is (C ¹ -C ⁴ ) alkyl, each R ^b is (C ¹ -C ⁴ ) alkyl that is the same or different, R ^a is (C ¹ -C ⁴ ) alkyl, the base is an alkoxide and the solvent is an organic solvent.

[0227] In particular embodiments, R ² is -CH ³ , each R ^b is -CH ³ , R ^a is -CH ³ , the base is sodium methoxide and the solvent is W-methyl-2-pyrrolidinone.

F. Condensation of F-1 with N-1 to form G-1:

[0228]

[0229] An equivalent of F-1 and a suitable solvent are combined in a reaction vessel, about 5 to 8 equivalents of a first acid and about 0.2 to about 0.5 equivalent of a second acid are added. The reaction can take place between about 20 and about 100 ° C.

[0230] The reaction is allowed to continue for about 2 to about 5 hours, after which about 1.5 equivalents of N-1 and about 2 to about 3 equivalents of a base are slowly introduced into the reaction vessel. Once the addition is complete, the reaction is allowed to progress for at least about 1 hour.

[0231] Water and an additional solvent are added to the reaction vessel and G-1 is extracted and purified by any suitable method known in the art, including, but not limited to, solvent extraction, silica gel chromatography and crystallization

[0232] In particular embodiments, the solvent is a non-protic polar organic solvent, such as, but not limited to, tetrahydrofuran, acetonitrile, diisopropyl ether, methyl ferc-butyl ether, N, N-dimethylformamide, N, N- dimethylacetamide, 1,4-dioxane or N-methyl-2-pyrrolidinone, or mixtures thereof. In certain embodiments, the solvent is a mixture of one, two or three, or in certain embodiments, a mixture of one or two of the following solvents: tetrahydrofuran, acetonitrile, diisopropyl ether, methyl ferc-butyl ether, N, N-dimethylformamide ., N, N- dimethylacetamide, 1,4-dioxane or N-methyl-2-pyrrolidinone. In further embodiments, the solvent is acetonitrile.

[0233] In certain embodiments, the first acid is an organic acid, an organic carboxylic acid or an inorganic acid. In certain embodiments, the first acid is an organic acid. In certain embodiments, the first acid is an organic carboxylic acid. In certain embodiments, the first acid is an inorganic acid. Exemplary organic acids include, among others, methanesulfonic acid, trifluoromethanesulfonic acid and trifluoroacetic acid. Examples of organic carboxylic acids include, among others, acetic acid, formic acid, butyric acid, propionic acid and benzoic acid. Examples of inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid or sulfuric acid. In other additional embodiments, the first acid is acetic acid.

[0234] In certain embodiments, the second acid is an organic acid, an organic carboxylic acid or an inorganic acid. In certain embodiments, the second acid is an organic acid. In certain embodiments, the second acid is an organic carboxylic acid. In certain embodiments, the first acid is an inorganic acid. Exemplary organic acids include, but are not limited to, methanesulfonic acid, trifluoromethanesulfonic acid and trifluoroacetic acid. Exemplary inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid and sulfuric acid. Examples of organic carboxylic acids include, among others, acetic acid, formic acid, butyric acid, propionic acid or benzoic acid. In particular embodiments, the second acid is methanesulfonic acid or formic acid.

[0235] In certain embodiments, the first acid is acetic acid and the second acid is methanesulfonic acid.

[0236] In certain embodiments, the first acid and the second acid are the same acid. In yet other embodiments, the first acid and the second acid are formic acid or acetic acid.

[0237] In certain embodiments, N-1 is in solution when added to the reaction mixture.

[0238] In other embodiments, L is -CH ² -CH ² -, that is, N-1 is (1R, 3S) -3-aminocyclopentan-1-ol:

In some embodiments, N-1 is

(3-aminocyclopentanol).

[0239] In particular embodiments, N-1 is a salt or co-crystal. Suitable salts or co-crystals of N-1 include, but are not limited to, oxalic acid, hydrochloric acid, mandelic acid, R-mandelic acid and S-mandelic acid. Suitable salts or co-crystals of N-1 include, but are not limited to, benzoic acid, naproxen, S-naproxen and R-naproxen.

[0240] In additional embodiments, N-1 is

[0241] In other additional embodiments, N-1 is;

[0242] In certain embodiments, after the addition of the acid, the reaction is maintained at about 20 to about 90 ° C, about 20 to about 80 ° C, about 20 to about 70 ° C, about 20 to about 60 ° C , about 20 to about 50 ° C, about 20 to about 40 ° C, about 20 to about 30 ° C, about 30 to about 100 ° C, about 30 to about 90 ° C, about 30 to about 80 ° C, about 30 to about 70 ° C, about 30 to about 60 ° C, about 30 to about 50 ° C, about 30 to about 40 ° C, about 40 to about 100 ° C, about 40 to about 90 ° C, about 40 to approximately 80 ° C, approximately 40 to approximately 70 ° C, approximately 40 to approximately 60 ° C, approximately 40 to approximately 50 ° C, approximately 50 aa approximately 100 ° C, approximately 50 to approximately 90 ° C, approximately 50 to approximately 80 ° C, approximately 50 to approximately 70 ° C, approximately 50 to approximately 60 ° C, approximately 60 to approximately 100 ° C, approximately 60 to approximately 90 ° C, about 60 to about 80 ° C, about 60 to about 70 ° C, about 70 to about 80 ° C, or any subinterval between them. In other additional embodiments, after the addition of the acid (s), the reaction is maintained at about 65 to about 70 ° C, about 70 to about 75 ° C, about 75 to about 80 ° C, or any subinterval between them.

[0243] In particular embodiments, the solvent is acetonitrile, the first acid is an organic carboxylic acid, the second acid is an organic carboxylic acid and, after the addition of the acids, the reaction is maintained at about 70 to about 75 ° C.

[0244] In particular embodiments, the solvent is acetonitrile, the first acid is acetic acid, the second acid is methanesulfonic acid, after the addition of the acids, the reaction is maintained at about 70 to about 75 ° C, and N- 1 is

G. Deprotection of G-1 to form a compound of Formula I:

[0245]

[0246] A reaction vessel is charged with approximately one equivalent of G-1 and a suitable solvent. Approximately two or three equivalents of a metal salt, a Lewis acid or other reagent are added to the solution. The resulting suspension is stirred at about 40 to about 100 ° C for about ten minutes to about three hours. The reaction is stopped by the addition of an acid and then a compound of Formula I is extracted and purified by any suitable technique known in the art, such as, but not limited to, solvent extraction, preparative HPLC and crystallization.

[0247] In a particular embodiment, the solvent is a non-protic polar organic solvent such as, but not limited to, 2-methyl tetrahydrofuran, tetrahydrofuran, acetonitrile, diisopropyl ether, methyl ferc-butyl ether, N, N- dimethylformamide, N , N-dimethylacetamide, 1,4-dioxane, N-methyl-2-pyrrolidinone, or mixtures thereof. In a further embodiment, the solvent is acetonitrile.

[0248] In certain embodiments, G-1 reacts with at least one reagent selected from the group consisting of metal salts, Lewis acids, sodium ethanolate, sodium hexamethyldisiloxane, trifluoroacetic acid and combinations thereof.

[0249] In other embodiments, the metal salt is selected from the group consisting of magnesium bromide, lithium chloride, lithium bromide and lithium iodide. In other additional embodiments, the metal salt is lithium chloride.

[0250] In particular embodiments, Lewis acid is selected from the group consisting of methyl boron trifluoride methyl boron, boron trifluoride diethyl ether, boron trifluoride dibutyl etherate, aluminum chloride, aluminum bromide, boron trichloride , boron tribromide, chlorotrimethylsilane, iodotrimethylsilane, palladium and boron trifluoride diethyl ether. In certain embodiments, Lewis acid is selected from the group consisting of chlorotrimethylsilane, iodotrimethylsilane, sodium ethanethiolate, sodium hexamethyldisiloxane, palladium, diethyl boron trifluoride etherate and trifluoroacetic acid.

[0251] In particular embodiments, other reagents suitable for facilitating conversion are sodium ethanethiolate, sodium hexamethyldisiloxane and trifluoroacetic acid.

[0252] In particular embodiments, deprotection of G-1 to form a compound of Formula I takes place in the presence of about two to about three equivalents of a reagent selected from the group consisting of: magnesium bromide, lithium chloride, bromide lithium, lithium iodide, boron methyl trifluoride ethyl, boron trifluoride diethyl etherate, boron trifluoride dibutyl etherate, aluminum chloride, aluminum bromide, boron trichloride, boron tribromide, chlorotrimethylsilane, iodotrimethyl silane, boron trifluoride diethyl etherate, chlorotrimethylsilane, iodotrimethylsilane, ethanoethiolate, hexamethyldisiloxane, palladium, boron trifluoride diethyl etherate, and trifluoroacetic acid.

[0253] In certain embodiments, the reaction proceeds at about 40 to about 50 ° C, about 40 to about 60 ° C, about 40 to about 70 ° C, about 50 to about 60 ° C, about 50 to about 70 ° C ., about 50 to about 80 ° C, about 60 to about 70 ° C, about 60 to about 80 ° C, or any sub-interval between them. In particular embodiments, the reaction proceeds at approximately 50 ° C.

[0254] In particular embodiments, the solvent is acetonitrile, the metal salt is magnesium bromide, and the reaction proceeds at approximately 50 ° C.

H. Hydrolysis of F-1 to produce a compound of Formula II:

[0255]

[0256] A reaction vessel is charged with approximately one equivalent of F-1 and a solution of approximately ten to fifteen parts of a first organic solvent and approximately 3 to 8 parts of water is prepared. Approximately two equivalents of a base are added to the solution. The resulting suspension is stirred at about 0 to about 50 ° C for about 14 to about 17 hours. The conversion can be monitored by any suitable method known in the art, such as, but not limited to, H ^p LC.

[0257] Water and a second organic solvent are added to the suspension and the pH is adjusted to approximately pH 3 by the dropwise addition of a suitable acid. The product, a compound of Formula II, can then be extracted and optionally purified by any suitable technique known in the art, such as, among others, solvent extraction, silica gel chromatography and crystallization.

[0258] In certain embodiments, the first organic solvent is an alcoholic solvent or a polar organic solvent. In certain embodiments, the first organic solvent is an alcoholic solvent. In certain embodiments, the first organic solvent is a polar organic solvent. Exemplary alcoholic solvents include, without limitation, methanol, ethanol, n-propanol, 2-propanol, butanol and ferc-butanol. Exemplary polar organic solvents include, but are not limited to, W, A / -dimethylformamide, W, W-dimethylacetamide, 1,4-dioxane and W-methyl-2-pyrrolidinone. In particular embodiments, the first organic solvent is methanol.

[0259] In other embodiments, the base is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate and potassium carbonate. In other additional embodiments, the base is lithium hydroxide monohydrate.

[0260] In certain embodiments, the reaction proceeds at about 10 to about 50 ° C, about 10 to about 40 ° C, about 10 to about 30 ° C, about 10 to about 20 ° C, about 20 to about 50 ° C , about 20 to about 40 ° C, about 20 to about 30 ° C, about 30 to about 50 ° C, about 30 to about 40 ° C, about 40 to about 50 ° C, or any sub-interval between them. In particular embodiments, the reaction proceeds at room temperature. In further embodiments, the reaction proceeds from about 18 to about 23 ° C.

[0261] In particular embodiments, the base is lithium hydroxide monohydrate, the reaction proceeds from about 10 to about 50 ° C and the first organic solvent is methanol.

[0262] In particular embodiments, the base is lithium hydroxide monohydrate, the reaction proceeds from about 18 to about 23 ° C and the first organic solvent is methanol.

I. Preparation of BB-1 from b-1 and Q-1:

[0263]

[0264] Approximately one equivalent of b-1 and eight to twelve equivalents of Q-1 are added to a reaction vessel and dissolved in a suitable organic solvent. The solution is then heated to about 85 to about 115 ° C and allowed to proceed for about two to six hours, after which the reaction is cooled to room temperature. BB-1 is then purified using techniques known in the art, such as, for example, silica gel chromatography.

[0265] In certain embodiments, the solvent is a non-polar aromatic solvent or a polar aprotic solvent. In certain embodiments, the solvent is a non-polar aromatic solvent. In certain embodiments, the solvent is a polar aprotic solvent. Examples of non-polar aromatics include, but are not limited to, toluene, xylene, chlorobenzene and dichlorobenzene. Examples of polar aprotic solvents include, among others, N, N- dimethylformamide, N, N-dimethylacetamide, 1,4-dioxane and N-methylpyrrolidinone. In other additional embodiments, the reaction can occur without additional solvent. In particular embodiments, the solvent is toluene.

[0266] In certain embodiments, the reaction proceeds at about 85 to about 105 ° C, about 85 to about 95 ° C, about 95 to about 105 ° C, about 95 to about 115 ° C, about 105 to about 115 ° C , about 100 to about 105 ° C, about 105 to about 110 ° C, about 110 to about 115 ° C, or any subinterval between them.

[0267] In particular embodiments, the reaction proceeds from about 95 to about 115 ° C, and the solvent is toluene.

[0268] In particular embodiments, the reaction proceeds from about 110 to about 115 ° C, and the solvent is toluene.

J. Preparation of C-1 from BB-1

[0269]

[0270] In a reaction vessel, approximately 1 equivalent of BB-1 and approximately 1 to approximately 3 equivalents of J-1 are combined. The compounds are dissolved in a non-protic polar solvent or an aromatic solvent. In certain embodiments, the compounds that dissolve are suspended in a non-protic polar solvent. In certain embodiments, the compounds are dissolved in an aromatic solvent. Exemplary polar non-protic solvents include, but are not limited to, acetonitrile, N, N-dimethylformamide, N, N- dimethylacetamide, 1,4-dioxane and N-methyl-2-pyrrolidinone. Exemplary aromatic solvents include, but are not limited to, pyridine, toluene, xylene, benzene and chlorobenzene. In other further embodiments, the compounds are dissolved in a solvent mixture comprising one or more non-protic polar solvents and / or one or more aromatic solvents. In certain embodiments, the compounds are dissolved in a solvent mixture comprising up to three, or up to two, polar non-protic solvents. In certain embodiments, the compounds are dissolved in a solvent mixture comprising up to three, or up to two, aromatic solvents. In certain embodiments, the compounds are dissolved in a solvent mixture comprising up to three, or up to two, solvents of the group consisting of acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, 1,4-dioxane. N-methyl-2-pyrrolidinone, pyridine, toluene, xylene, benzene and chlorobenzene. In another embodiment, the compounds are dissolved in toluene.

[0271] In particular embodiments, each Hal is independently -F or -Cl. In a particular embodiment, Hal is -F In certain embodiments, n = 1-3. In certain embodiments, n = 2. In certain embodiments, n = 3. In other embodiments, J-1 is

In certain embodiments, J-1 is

In additional embodiments, J-1 is

[0272] In other additional embodiments, J-1 is in the form of a salt or co-crystal, such as, but not limited to, a salt or co-crystal of hydrochloric acid or trifluoroacetic acid. In certain embodiments, J-1 is a salt or co-crystal of methanesulfonic acid.

[0273] In certain embodiments, the reaction proceeds at about 65 to about 115 ° C, about 75 to about 115 ° C, about 85 to about 115 ° C, about 95 to about 115 ° C, about 105 to about 115 ° C , about 65 to about 70 ° C, about 70 to about 80 ° C, about 80 to about 90 ° C, about 90 to about 100 ° C, about 100 to about 110 ° C, about 110 to about 115 ° C, or any subinterval between them.

[0274] In certain embodiments, the solvent is removed under reduced pressure. In particular embodiments, C-1 is extracted from the crude residue by solvent extraction. The resulting crude material is purified using any suitable technique, such as silica gel chromatography or crystallization to produce C-1.

[0275] In particular embodiments, the compounds are dissolved in an aromatic solvent, J-1 is

and the reaction proceeds from about 65 to about 115 ° C.

[0276] In particular embodiments, the compounds are dissolved in toluene, J-1 is

and the reaction proceeds from about 100 to about 110 ° C.

K. Preparation of C-1 from b-1.J-1

[0277]

[0278] b-1.J-1, a solvent and an acid are combined in a reactor under conditions effective to produce C-1.

[0279] In certain embodiments, the acid is absent. In certain embodiments, the acid is a protic acid or a Lewis acid. In certain embodiments, protic acids include, among others, trifluoroacetic acid, trichloroacetic acid, dichloroacetic acid, chloroacetic acid, acetic acid, formic acid, hydrochloric acid, hydrobromic acid, toluenesulfonic acid and methanesulfonic acid. In certain embodiments, Lewis acids include, but are not limited to, zinc chloride, magnesium bromide, magnesium triflate, copper triflate and scandium triflate. In particular embodiments, the acid is trifluoroacetic acid.

[0280] In certain embodiments, about 10 equivalents, about 5 equivalents, about 1 equivalent, or about 0.1 equivalents of acid are used in the reaction of b-1.J-1 to form C-1.

[0281] In certain embodiments, the solvent is toluene, heptane, water, 2-methyltetrahydrofuran, isopropyl acetate, W, W-dimethylformamide, W-methyl-2-pyrrolidinone, methyl-ferc-butyl ether, dimethylsulfoxide, n-butanol ., acetonitrile, acetone, or a mixture thereof. In a particular embodiment, the solvent is acetonitrile.

[0282] In certain embodiments, b-1.J-1 is in a concentration ranging from about 2 to 40 ml / g, about 2 to 20 ml / g, about 5 to 15 ml / g. In a particular embodiment, b-1.J-1 is in a concentration of approximately 10 ml / g.

[0283] In certain embodiments, the reaction mixture is heated to a temperature between about 20 and 110 ° C, about 30 and 90 ° C, about 40 and 80 ° C, about 50 and 70 ° C, about 55 and 65 ° C, or about 58 and 61 ° C. In a particular embodiment, the reaction mixture is heated to approximately 60 ° C.

[0284] In certain embodiments, other additives are added to the reaction. In certain embodiments, the additives include, among others, lithium chloride, sodium chloride and potassium chloride.

[0285] In certain embodiments, b-1.J-1 is charged into the reactor in a single portion at approximately 20 ° C followed by heating. In certain embodiments, b-1.J-1 is charged into the reactor in portions for 1 hour during heating.

[0286] In certain embodiments, the reaction is heated for about 1 to 24 hours, for about 2 to 12 hours, or for about 3 to 6 hours. In a particular embodiment, the reaction is heated for approximately 2.5 hours.

[0287] In certain embodiments, the product formed is extracted and optionally purified by any suitable technique known in the art, such as, but not limited to, solvent extraction, chromatography, crystallization or a combination thereof.

[0288] In certain embodiments, the reaction is cooled and the reactor contents are partially distilled.

[0289] In certain embodiments, the organic phase is washed at least once with an aqueous solution. In certain embodiments, the aqueous solution contains approximately 23% NaCl, approximately 1.5% H2SO4 and approximately 76% water. In certain embodiments, the aqueous solution contains approximately 20% NaCl.

[0290] In certain embodiments, a solution of the product is seeded with C-1 seeds that had previously been isolated. In certain embodiments, solid C-1 is isolated by filtration.

[0291] In particular embodiments, each Hal is independently -F or -Cl. In a particular embodiment, each Hal is -F. In certain embodiments, n = 1-3. In certain embodiments, n = 2. In certain embodiments, n = 3. In other embodiments, J-1 is

In certain embodiments, J-1 is

In additional embodiments, J-1 is

[0292] In certain embodiments, R ^a is (C ¹ -C ⁴ ) alkyl, aryl (C ^e- C ^io ) or aryl (C ⁶ -C ¹⁰ ) aryl (C1C4). In certain embodiments, R ^a is (C ¹ -C ⁴ ) alkyl. In certain embodiments, R ^a is methyl.

[0293] In particular embodiments, R ^a is (C ¹ -C ⁴ ) alkyl, the solvent is acetonitrile, the reaction mixture is heated to about 60 ° C, and J-1 is

[0294] In particular embodiments, Ra is methyl, the solvent is acetonitrile, the reaction mixture is heated to approximately 60 ° C, and J-1 is

L. Enamine formation from C-1 to provide D-1

[0295]

[0296] To a solution of C-1 and an acid in a solvent, about 0.5 to about 1.5 equivalents of an alkylated formamide acetal are added under conditions effective to produce D-1.

[0297] In particular embodiments, an equivalent of C-1 is combined with approximately 1.1 equivalents of the alkylated formamide acetal.

[0298] In certain embodiments, the alkylated formamide acetal is selected from the group consisting of N, N- dimethylformamide acetyl dimethyl, N, N-dimethylformamide diethyl acetal, N, N-dimethylformamide diisopropylacetal, N, N- diethylformamide dimethyl acetal, and N, N- diisopropylformamide dimethyl acetal. In a particular embodiment, the alkylated formamide acetal is N, N-dimethylformamide dimethyl acetal.

[0299] In certain embodiments, the solvent is dichloromethane, tetrahydrofuran, acetone, acetonitrile, ethyl acetate, isopropyl acetate, toluene, N, N-dimethylformamide, N, N-dimethylacetamide, 2-methyltetrahydrofuran or N-methyl-2- pyrrolidone In a particular embodiment, the solvent is 2-methyltetrahydrofuran.

[0300] In certain embodiments, the acid is an organic acid. In certain embodiments, the organic acid includes, but is not limited to, trifluoroacetic acid, formic acid, acetic acid, sulfuric acid, trifluoroacetic acid, trichloroacetic acid and perfluoropropionic acid. In certain embodiments, the acid is a mixture comprising up to three, or up to two, organic acids. In a particular embodiment, the acid is trifluoroacetic acid.

[0301] In certain embodiments, the reaction mixture is heated to an internal temperature of approximately 40 ° C before adding the alkylated formamide acetal.

[0302] In certain embodiments, the reaction takes place between approximately 0 and 75 ° C, approximately between 10 and 60 ° C, between approximately 20 and 50 ° C, between approximately 40 and 50 ° C, or between approximately 30 and 40 ° C . In particular embodiments, the reaction proceeds at room temperature. In further embodiments, the reaction proceeds at approximately 40 ° C.

[0303] In certain embodiments, the reaction proceeds for about 0.1 hours to about 12 hours, for about 0.1 hours to about 6 hours, for about 0.1 hour to about 3 hours, from about 0.1 hour to about 1 hour, or about 0.2 hours. hour to about 0.5 hour.

[0304] In certain embodiments, D-1 is extracted and purified by any suitable method known in the art, which includes, among others, solvent extraction, crystallization and chromatography.

[0305] In certain embodiments, D-1 seeds are added and the mixture is stirred. In certain embodiments, the mixture is stirred at approximately 40 ° C for at least 1 hour.

[0306] In certain embodiments, about 0.2 to 0.6 equivalents of alkylated formamide acetal are added and the reaction mixture is stirred for at least about 25 minutes. The reaction mixture is cooled to room temperature and allowed to stir for about 12 hours.

[0307] In certain embodiments, the contents of the reactor are filtered and the filter cake is rinsed with a solvent and dried to obtain D-1. In certain embodiments, the solvent is a combination of 2-methyltetrahydrofuran and heptanes.

[0308] In particular embodiments, each Hal is independently -F or -Cl. In a particular embodiment, each Hal is -F In certain embodiments, n = 1-3. In certain embodiments, n = 2. In certain embodiments, n = 3.

[0309] In certain embodiments, Ra is (C1-C4) alkyl, (C6-C10) aryl or (C6-C10) aryl (C1C4) aryl. In certain embodiments, Ra is (C1-C4) alkyl. In certain embodiments, Ra is methyl.

[0310] In certain embodiments, each Rb is independently (C1-C4) alkyl, aryl (C6-C10) or aryl (C6-C10) (C1C4). In certain embodiments, each Rb is independently (C1-C4) alkyl. In certain embodiments, Rb is methyl.

[0311] In particular embodiments, Rb is (C1-C4) alkyl, Ra is (C1-C4) alkyl, the alkylated formamide acetal is N, N-dimethylformamide dimethylacetal, the solvent is 2-methyltetrahydrofuran, the reaction to about 10 to about 60 ° C, the acid is trifluoroacetic acid, each Hal is -F and n = 3.

[0312] In particular embodiments, Rb is methyl, Ra is methyl, the alkylated formamide acetal is N, N- dimethylformamide dimethyl acetal, the solvent is 2-methyltetrahydrofuran, the reaction proceeds at approximately 40 ° C, the acid is trifluoroacetic acid , Hal is -F and n = 3.

M. Formation of F-1 from D-1 to E-1

[0313]

[0314] To a solution of D-1 in a solvent, approximately 1.1 equivalents of K-1 are added under conditions effective to produce E-1.

[0315] In certain embodiments, the solvent is an alcohol solvent such as, but not limited to, ethanol, npropanol, 2-propanol, butanol, methanol and ferc-butanol, or aprotic polar organic solvents such as, for example, 2-methyl tetrahydrofuran, tetrahydrofuran, acetone, acetonitrile, W, A / -dimethylformamide, W, W-dimethylacetamide, 1,4-dioxane and A / -methyl-2-pyrrolidinone. In particular embodiments, the solvent is methanol.

[0316] In certain embodiments, K-1 is an aminoacetaldehyde acetal such as, but not limited to, aminoacetaldehyde diethylacetal, aminoacetaldehyde dipropylacetal, dimethyl acetaldehyde aminoacetaldehyde, and aminoacetaldehyde acetacetaldehyde. In certain embodiments, K-1 is dimethyl acetal aminoacetaldehyde.

[0317] In certain embodiments, the reaction proceeds at about 10 to 60 ° C, about 10 to 50 ° C, about 10 to 40 ° C, about 10 to 30 ° C, about 10 to 20 ° C, 20 to 60 ° C, approximately 20 to 50 ° C, approximately 20 to 40 ° C, approximately 20 to 30 ° C, approximately 30 to 60 ° C, approximately 30 to 50 ° C, approximately 30 to 40 ° C, approximately 40 to 60 ° C , approximately 40 to 50 ° C, approximately 50 to 60 ° C, or any subinterval between them. In particular embodiments, the reaction proceeds at room temperature. In further embodiments, the reaction proceeds from about 16 ° C to about 23 ° C.

[0318] In certain embodiments, the reaction is stirred for about 0.1 to about 12 hours, about 0.5 to about 4 hours, about 1 to about 2 hours.

[0319] Once the reaction has progressed sufficiently to produce E-1, M-1 is added to the reaction mixture.

[0320] In certain embodiments, about 1 to about 10 or about 1 to about 5 equivalents of M-1 are added. In a particular embodiment, about 5 equivalents of M-1 are added.

[0321] In certain embodiments, M-1 is dimethyl oxalate, diethyl oxalate, dipropyl oxalate or dibutyl oxalate. In a particular embodiment, M-1 is dimethyl oxalate.

[0322] The reaction mixture is stirred at a temperature sufficient to achieve the dissolution of M-1. In certain embodiments, the reaction mixture is stirred at about 20-80 ° C, at about 20-70 ° C, at about 20-60 ° C, at about 30-60 ° C, at about 40-50 ° C or around 45 ° C.

[0323] In certain embodiments, a base is added to the reaction mixture after the addition of M-1.

[0324] In certain embodiments, the base is a metal hydride, an alkoxide, an inorganic carbonate or a bis (trialkylsilyl) amide. In certain embodiments, the base is a metal hydride. In certain embodiments, the base is an alkoxide. In certain embodiments, the base is an inorganic carbonate. In certain embodiments, the base is a bis (trialkylsilyl) amide. Examples of metal hydrides include, among others, lithium hydride, sodium hydride and potassium hydride. Exemplary alkoxides include, but are not limited to, sodium methoxide, sodium ferc-butoxide, sodium ethoxide, potassium ferc-butoxide, potassium ethoxide, sodium ferc-pentoxide and lithium ferc-butoxide.

Exemplary bis (trialkylsilyl amide) bases include, but are not limited to, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide and potassium bis (trimethylsilyl) amide. Exemplary carbonates include, but are not limited to, lithium carbonate, sodium, potassium and cesium.

[0325] In additional embodiments, the base is a mixture of at least one of the above bases. In certain embodiments, the base is a mixture of up to three, or up to two, metal hydrides. In certain embodiments, the base is a mixture of up to three, or up to two, alkoxides. In certain embodiments, the base is a mixture of up to three, or up to two, metal bis (trialkylsilyl) amides. In certain embodiments, the base is a mixture of up to three or up to two of the following bases: lithium hydride, sodium hydride, potassium hydride, sodium methoxide, sodium ferc-butoxide, sodium ethoxide, ferc-butoxide potassium, potassium ethoxide, sodium ferc-pentoxide, lithium ferc-butoxide, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide and potassium bis (trimethylsilyl) amide.

[0326] In particular embodiments, the base is sodium methoxide. In particular embodiments, the base is sodium methoxide in methanol solution.

[0327] In certain embodiments, after the addition of the base, the reaction is heated to about 20 to 80 ° C, 20 to 70 ° C, about 20 to 60 ° C, about 20 to 50 ° C, about 20 to 40 ° C, approximately 20 to 30 ° C, approximately 30 to 80 ° C, approximately 30 to 70 ° C, approximately 30 to 60 ° C, approximately 30 to 50 ° C, approximately 30 to 40 ° C, approximately 40 to 80 ° C, approximately 40 to 70 ° C, approximately 40 to 60 ° C, approximately 40 to 50 ° C, approximately 50 to 80 ° C, approximately 50 to 70 ° C, approximately 50 to 60 ° C, approximately 60 to 80 ° C, about 60 to 70 ° C, about 70 to 80 ° C, or any subinterval between them. In a particular embodiment, the reaction is heated to about 42 to 48 ° C. In a particular embodiment, the reaction is heated to approximately 45 ° C.

[0328] In certain embodiments, the reaction is stirred for about 1 to about 24 hours, about 6 to about 24 hours, about 12 to about 20 hours, about 14 to about 18 hours.

[0329] In certain embodiments, the reaction is diluted with an aqueous solution and F-1 is extracted and purified by any suitable method known in the art, including, but not limited to, solvent extraction, crystallization and chromatography in Silica gel.

[0330] In certain embodiments, the temperature is reduced to about 34-37 ° C over the course of about 1 hour, optionally charged with F-1 seed crystals and allowed to age for about 1-2 hours. At this point, water is added and the temperature is reduced to approximately 18-22 ° C for 1 hour. The resulting suspension is filtered.

[0331] In certain embodiments, liquors are recycled to displace the solids left in the reactor. The solids collected in the filter are then washed with a 1: 1 mixture of water and methanol, followed by water. The collected wet cake is dried in a vacuum oven at about 36-42 ° C for about 16 hours, providing F-1.

[0332] In certain embodiments, R ¹ is (C ¹ -C ⁴ ) alkyl, aryl (C ⁶ -C ¹⁰ ), or aryl (C ¹ -C ¹⁰ ) aryl (C ¹ -C ⁴ ). In certain embodiments, R ¹ is C ¹ -C ⁴ alkyl. In further embodiments, R ¹ is -CH ³ , that is, K-1 is amino acetaldehyde dimethyl acetal.

[0333] In certain embodiments, R ² is (C ¹ -C ⁴ ) alkyl, aryl (C ⁶ -C ¹⁰ ), or aryl (C ¹ -C ¹⁰ ) aryl (C ¹ -C ⁴ ). In certain embodiments, R ² is C ¹ -C ⁴ alkyl. In certain embodiments, R ² is -CH ³ .

[0334] In particular embodiments, each Hal is independently -F or -Cl. In a particular embodiment, Hal is -F In certain embodiments, n = 1-3. In certain embodiments, n = 2. In certain embodiments, n = 3.

[0335] In certain embodiments, R ^a is (C ¹ -C ⁴ ) alkyl, aryl (C ⁶ -C ¹⁰ ), or aryl (C ⁶ -C ¹⁰ ) aryl (C ¹ C ⁴ ). In certain embodiments, R ^a is (C ¹ -C ⁴ ) alkyl. In certain embodiments, R ^a is methyl.

[0336] In certain embodiments, each R ^b is independently (C ¹ -C ⁴ ) alkyl, aryl (C ⁶ -C ¹⁰ ) or aryl (C ⁶ -C ¹⁰ ) (C ¹ C ⁴ ) alkyl. In certain embodiments, each R ^b is independently (C ¹ -C ⁴ ) alkyl. In certain embodiments, R ^b is methyl.

[0337] In particular embodiments, R ^b is methyl, R ^a is (C ¹ -C ⁴ ) alkyl, each Hal is -F, n = 3, R ² is (C ¹ -C ⁴ ) alkyl, R ¹ is alkyl (C ¹ -C ⁴ ), the solvent is an alcoholic solvent, K-1 is aminoacetaldehyde dimethylacetal, the first reaction proceeds from about 2 to about 40 ° C, the second reaction is heated to about 20 to about 80 ° C, the base is an alkoxide and M-1 is dimethyl oxalate

[0338] In particular embodiments, R ^b is methyl, R ^a is methyl, Hal is -F, n = 3, R ² is -CH ³ , R ¹ is -CH ³ , the solvent is methanol, K-1 is aminoacetaldehyde dimethylacetal, the first reaction proceeds at approximately 16 at about 23 ° C, the second reaction is heated to about 45 ° C, the base is sodium methoxide and M-1 is dimethyl oxalate

N. Acetal hydrolysis of F-1 to form FF-1

[0339]

[0340] To a solution of F-1 in a solvent, approximately 0.1 to 1 equivalent of a first acid and approximately 2 to 20 equivalents of a second acid are added under conditions effective to produce FF-1.

[0341] In some embodiments, approximately 0.1 to 0.5 equivalents of the first acid are added. In particular embodiments, approximately 0.1 equivalents of the first acid are added.

[0342] In some embodiments, the solvent is a polar organic solvent or a weak protic acid. In some embodiments, the polar organic solvent includes, but is not limited to propionitrile, tetrahydrodurane, 1,4-dioxane, acetonitrile and ethyl acetate. In some embodiments, weak protic acid includes, but is not limited to formic acid, propionic acid and butyric acid. In a particular embodiment, the solvent is acetonitrile.

[0343] In some embodiments, the first acid is a strong protic acid that includes, among others, methanesulfonic acid, sulfuric acid, hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid and camphorsulfonic acid.

[0344] In a particular embodiment, the first acid is p-toluenesulfonic acid. In a particular embodiment, the first acid is p-toluenesulfonic acid monohydrate.

[0345] In some embodiments, the second acid is a weak protic acid that includes, but is not limited to, acetic acid, formic acid, propionic acid and butyric acid. In a particular embodiment, the second acid is acetic acid.

[0346] The reaction is then heated to about 20 to 120 ° C, about 40 to 100 ° C, about 60 to 80 ° C, or about 70 to 80 ° C. In a particular embodiment, the reaction is heated to approximately 75 ° C.

[0347] In certain embodiments, the reaction is stirred for about 1 to about 24 hours, for about 4 to about 14 hours, for about 8 to about 10 hours.

[0348] In certain embodiments, water is added to the reaction mixture.

[0349] In certain embodiments, the product formed is extracted and, optionally, purified by any suitable technique known in the art, such as, but not limited to, solvent extraction, chromatography, crystallization or a combination thereof.

[0350] In certain embodiments, the mixture is concentrated under reduced pressure to remove the solvent. The resulting suspension is aged at room temperature for approximately 2 hours, filtered and washed with water. The cake is dried in a vacuum oven at 50 ° C for at least 10 hours to give FF-1.

[0351] In certain embodiments, R ¹ is (C ¹ -C ⁴ ) alkyl, aryl (C ⁶ -C ¹⁰ ) or aryl (C ⁶ -C ¹⁰ ) aryl (C ¹ -C ⁴ ). In certain embodiments, R ¹ is C ¹ -C ⁴ alkyl. In additional embodiments, R ¹ is -CH ³ .

[0352] In certain embodiments, R ² is (C ¹ -C ⁴ ) alkyl, aryl (C ⁶ -C ¹⁰ ), or aryl (C ¹ -C ¹⁰ ) aryl (C ¹ -C ⁴ ). In certain embodiments, R ² is C ¹ -C ⁴ alkyl. In certain embodiments, R ² is -CH ³ .

[0353] In particular embodiments, each Hal is independently -F or -Cl. In a particular embodiment, Hal is -F In certain embodiments, n = 1-3. In certain embodiments, n = 2. In certain embodiments, n = 3.

[0354] In certain embodiments, R ^a is (C ¹ -C ⁴ ) alkyl, aryl (C ⁶ -C ¹⁰ ) or aryl (C ⁶ -C ¹⁰ ) aryl (C ¹ C ⁴ ). In certain embodiments, R ^a is (C ¹ -C ⁴ ) alkyl. In certain embodiments, R ^a is methyl.

[0355] In particular embodiments, R ^a is (C ¹ -C ⁴ ) alkyl, each Hal is -F, n = 3, R ² is (C ¹ -C ⁴ ) alkyl, R ¹ is (C ¹ -C) alkyl ⁴ ), the reaction is heated to about 20 to 120 ° C, the first acid is p-toluenesulfonic acid, the second acid is acetic acid and the solvent is acetonitrile.

[0356] In particular embodiments, R ^a is methyl, Hal is -F, n = 3, R ² is -CH ³ , R ¹ is -CH ³ , the reaction is heated to approximately 75 ° C, the first acid is acidic p-toluenesulfonic, the second acid is acetic acid, and the solvent is acetonitrile.

O. Cyclization of FF-1 and N-1 to form G-1

[0357]

[0358] The starting material FF-1, N-1, or one of its salts or the same, and an additive are combined with a solvent under conditions effective to produce G-1.

[0359] In certain embodiments, the additive is a carboxylate salt such as, but not limited to, sodium acetate, potassium acetate, lithium acetate, sodium propionate and potassium propionate. In certain embodiments, the additive is a carbonate such as, among others, sodium carbonate, potassium carbonate, lithium carbonate and cesium carbonate. In certain embodiments, the additive is a water eliminator such as, among others, molecular sieves, trimethyl orthoacetate and trimethyl orthoformate. In particular embodiments, the additive is potassium acetate.

[0360] In certain embodiments, about 1 to about 2 or about 1 to about 1.5 equivalents of N-1 or one of its salts or co-crystal is used.

[0361] In certain embodiments, about 1 to about 5 equivalents of additive are used. In particular embodiments, approximately 2.5 equivalents of additive are added.

[0362] In certain embodiments, the solvent is acetonitrile, ethyl acetate, toluene, 2-methyl tetrahydrofuran, isopropyl acetate, dichloromethane or a mixture thereof. In particular embodiments, the solvent is dichloromethane.

[0363] In certain embodiments, the reaction is stirred at about 0 to about 40 ° C, about 10 to about 30 ° C, about 15 to about 25 ° C, about 20 ° C.

[0364] In certain embodiments, G-1 is extracted and optionally purified by any suitable technique known in the art, such as, but not limited to, solvent extraction, chromatography, crystallization or a combination thereof.

[0365] In particular embodiments, the reaction mixture is washed with an aqueous solution and evaporated to dryness. In particular embodiments, the residue is dissolved in dimethylformamide and the resulting solution is added to water for approximately 2 hours, while stirring. The product suspension is aged at approximately 20 ° C for approximately 12 hours and filtered. The product cake is washed with water and dried to obtain G-1.

[0366] In certain embodiments, N-1 is in solution when added to the reaction mixture.

[0367] In other embodiments, L is -CH ² -CH ² -.

[0368] In particular embodiments, N-1 is (1R, 3S) -3-aminocyclopentan-1-ol:

[0369] In particular embodiments, N-1 is a free base or is synthesized and used without isolation.

[0370] In particular embodiments, N-1 is a salt or co-crystal. Suitable salts or co-crystals of N-1 include, but are not limited to, benzoic acid, acetic acid, fumaric acid, methanesulfonic acid, p-toluenesulfonic acid, oxalic acid, hydrochloric acid, naproxen, S-naproxen, R- naproxen, mandelic acid, R-mandelic acid and S-mandelic acid.

[0371] In additional embodiments, N-1 is

[0372] In particular embodiments, N-1 is a salt or co-crystal with benzoic acid.

[0373] In particular embodiments, N-1 is

[0374] In particular embodiments, each Hal is independently -F or -Cl. In a particular embodiment, each Hal is -F In certain embodiments, n = 1-3. In certain embodiments, n = 2. In certain embodiments, n = 3.

[0375] In certain embodiments, R ² is (C ¹ -C ⁴ ) alkyl, aryl (C ⁶ -C ¹⁰ ), or aryl (C ¹ -C ¹⁰ ) aryl (C ¹ -C ⁴ ). In certain embodiments, R ² is C ¹ -C ⁴ alkyl. In certain embodiments, R ² is -CH ³ .

[0376] In certain embodiments, R ^a is (C ¹ -C ^4), aryl (C -C ^io) aryl or (C ^e -C ^{í o)} aryl (C ¹ C ^4). In certain embodiments, R ^a is (C ¹ -C ⁴ ) alkyl. In certain embodiments, R ^a is methyl.

[0377] In particular embodiments, R ^a is (C ¹ -C ⁴ ) alkyl, each Hal is -F, n = 3, R ² is -CH ³ , N-1 is

The solvent is dichloromethane, the reaction is stirred at about 0 to about 40 ° C and the additive is potassium acetate.

[0378] In particular embodiments, R ^a is methyl, Hal is -F, n = 3, R ² is -CH ³ , N-1 is

The solvent is dichloromethane, the reaction is stirred at approximately 20 ° C and the additive is potassium acetate. P. Conversion of (-) - Vince lactam from b-1 to a-1

[0379]

[0380] A catalyst, a solvent and (-) - Lactamic Vince are stirred in a reactor, which is purged with an inert gas. A source of hydrogen is added.

[0381] In certain embodiments, the source of hydrogen is formic acid, hydrazine, dihydronaphthalene, dihydroanthracene, hydrogen gas or Hantzch ester and isopropanol. In particular embodiments, the source of hydrogen is hydrogen gas.

[0382] In certain embodiments, the catalyst is a platinum catalyst such as PtO2, a nickel catalyst such as Raney nickel, a rhodium catalyst such as RhCl (PPh3) 3, a palladium catalyst, a ruthenium catalyst such as Nyori catalyst or an iridium Catalyst as the catalyst of Crabtree. In some embodiments, the catalyst is selected from the group consisting of Pd / C, PtO2, Raney nickel, RhCl (PPh3) 3, Nyori catalyst and Crabtree catalyst. In particular embodiments, the catalyst is Pd / C.

[0383] In certain embodiments, the solvent is a polar aprotic solvent such as THF, 2-MeTHF, dioxane, diethyl ether, diisopropyl ether, DME, MTBE, CPME, EtOAc and DCM. In certain embodiments, the solvent is a polar protic solvent such as methanol, ethanol, n-butanol and isopropanol. In particular embodiments, the solvent is 2-methyltetrahydrofuran.

[0384] In certain embodiments, the reaction is stirred at about 0 to 65 ° C, about 10 to 55 ° C, about 15 to 45 ° C, about 20 to 40 ° C, about 25 to 35 ° C.

[0385] In certain embodiments, the reactor is maintained at about 0.30 to about 0.35 MPa.

[0386] In certain embodiments, the reaction takes place for about 1 to about 24 hours, about 1 to about 12 hours, about 3 to about 9 hours, about 6.5 hours.

[0387] In certain embodiments, the product formed is extracted and optionally purified by any suitable technique known in the art, such as, but not limited to, solvent extraction, chromatography, crystallization or a combination thereof.

[0388] In certain embodiments, the reaction is filtered through celite and washed with 2-MeTHF to produce the hydrogenated product in solution.

[0389] In certain embodiments, a second catalyst is added to a solution of the hydrogenated product, as well as an activated source for a protecting group.

[0390] In certain embodiments, the second catalyst is a compound containing nucleophilic amines such as imidazole, derivatives of 4-dimethylaminopyridine, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] undec -7-ene, and pyridine, or a compound containing nucleophilic phosphine such as triphenylphosphine. In particular embodiments, the second catalyst is 4-dimethylaminopyridine (DMAP).

[0391] In certain embodiments, the activated source of the protecting group is Boc2O. In particular embodiments, Boc2O is prepared in solution in 2-MeTHF.

[0392] In certain embodiments, the protecting group is Boc.

[0393] In certain embodiments, the reaction occurs in a polar aprotic solvent such as THF, EtOAc, DCM, acetonitrile or 2-MeTHF. In particular embodiments, the reaction occurs in 2-MeTHF.

[0394] In certain embodiments, the reaction occurs at temperatures in the range of about 20 to 8 ° C, about 25 to 70 ° C, about 35 to 60 ° C, about 45 to 50 ° C.

[0395] In certain embodiments, the reaction occurs for about 0.5 to about 12 hours, about 1 to about 6 hours, about 1 to about 3 hours, about 2 hours.

[0396] In certain embodiments, the product formed is extracted and optionally purified by any suitable technique known in the art, such as, but not limited to, solvent extraction, chromatography, crystallization or a combination thereof.

[0397] In certain embodiments, the solution is concentrated and a second solvent is added.

[0398] In certain embodiments, the second solvent is a polar aprotic solvent such as THF, dioxane, DME, diisopropyl ether, diethyl ether, MTBE, CPME, 2-MeTHF and toluene. In particular embodiments, the second solvent is 2-MeTHF.

[0399] In certain embodiments, the solution is maintained at about -50 to 30 ° C, about -50 to 30 ° C, about -30 to 20 ° C, about -20 to 10 ° C, about -10 to 0 ° C.

[0400] After hydrogenation and addition of the PG protecting group, an R3M nucleophile is added to the reaction mixture.

[0401] In certain embodiments, the R3M nucleophile is an Grignard n-alkyl reagent such as ethylmagnesium halides, n-propylmagnesium halides and n-butylmagnesium halides or organolithium reagent such as lithium methyl, n-butyllithium and n- Hexylithium In particular embodiments, the nucleophile is methyl magnesium bromide.

[0402] In certain embodiments, R3M nucleophile is added, while maintaining the reaction within the desired temperature range, for about 1 to about 12 hours, about 3 to about 9 hours, about 5 to about 7 hours, about 6 hours . Once the addition is complete, the mixture is stirred for an additional period of about 0.5 to about 12 hours, about 0.5 to about 6 hours, about 0.5 to about 4 hours, about 1 to about 2 hours

[0403] In certain embodiments, the product formed is extracted and optionally purified by any suitable technique known in the art, such as, but not limited to, solvent extraction, chromatography, crystallization or a combination thereof.

[0404] In certain embodiments, after the addition of the R3M nucleophile, 15% aqueous AcOH is added while maintaining the temperature of about 0 to 5 ° C to adjust the pH to about 7. The layers are separated and the layer Organic is washed with water twice. The organic layer is concentrated at 4 to 5 volumes under reduced pressure at approximately <45 ° C. The solution is azeotropically distilled with 2-MeTHF. The final solution is concentrated under reduced pressure to approximately 2.5 to 3 volumes and n-heptane is added slowly while maintaining the temperature between 30 and 35 ° C. In certain embodiments, b-1 seeds are added and the mixture is stirred at about 30 to 35 ° C for about 5 to 10 hours.

[0405] In certain embodiments, additional n-heptane is added while maintaining the temperature of 30 to 35 ° C for approximately 5 h. The contents are cooled to a temperature of -5 to 0 ° C and maintained for about 1 to 2 hours. The product is collected by filtration, washed with n-heptane at a temperature of -5 to 0 ° C and dried under reduced pressure from 40 to 45 ° C to obtain b-1.

[0406] In particular embodiments, the source of hydrogen is hydrogen gas, the catalyst is a palladium catalyst, the solvent for hydrogenation is 2-methyltetrahydrofuran, the hydrogenation reaction is stirred at about 0 to about 65 ° C, the second Catalyst is a compound that contains nucleophilic amine, the activated source of the protective group is Boc2O, the protective reaction occurs in 2-MeTHF at approximately 25 to 70 ° C, the second solvent is 2-MeTHF, and the nucleophile is methyl bromide magnesium.

[0407] In particular embodiments, the source of hydrogen is hydrogen gas, the catalyst is Pd / C, the solvent for hydrogenation is 2-methyltetrahydrofuran, the hydrogenation reaction is stirred at approximately 25 to 35 ° C, the second catalyst is 4- Dimethylaminopyridine, the activated source of the protective group is Boc2O, the protective reaction occurs in 2-MeTHF at approximately 45 to 50 ° C, the second solvent is 2-MeTHF, and the nucleophile is methyl magnesium bromide.

Q. Conversion from b-1 to c-1

[0408]

[0409] To an solution of b-1 in a solvent, an oxidant is added and the reaction is stirred.

[0410] In certain embodiments, PG is a protective group. In certain embodiments, the PG protecting group is Boc.

[0411] In certain embodiments, the solvent is a polar aprotic solvent such as DCM, 1,2-dichloroethane, toluene, chlorobenzene, dichlorobenzene, chloroform, carbon tetrachloride and DMF, or a polar protic solvent such as water, acetic acid, methanol and ethanol. In particular embodiments, the solvent is toluene.

[0412] In certain embodiments, the oxidant is hydrogen peroxide, oxone, t-butyl hydrogen peroxide, trifluoroperacetic acid (TFPAA), nitroperbenzoic acid, monopermaleic acid (MPMA), monoperphthalic acid, monoperphthalic acid, acidic magnesium salt, acid persulfuric acid, peracetic acid, perbenzoic acid, a silylated peracid, benzeneperoxiselenic acid, sodium perborate, meta-chloroperoxybenzoic acid or a resin-bound peracid. In particular embodiments, the oxidant is meta-chloroperoxybenzoic acid (mCPBA).

[0413] In certain embodiments, mCPBA is added in several portions every 4 to 6 h.

[0414] In certain embodiments, the reaction is stirred within the temperature range of -10 to 50 ° C, 0 to 40 ° C, 10 to 45 ° C, 15 to 40 ° C, 20 to 35 ° C, 25 to 30 ° C

[0415] In certain embodiments, the reaction is stirred for 1 to 48 h, 6 to 36 h, 10 to 20 h.

[0416] In certain embodiments, the product formed is optionally extracted and purified by any suitable technique known in the art, such as, but not limited to, solvent extraction, chromatography, crystallization or a combination thereof.

[0417] In particular embodiments, 20% NaHSO3 is added, then 10% NaOH is added. The organic layer is washed with water and concentrated to provide the oxidized product in solution.

[0418] In a solution of the oxidized product, water, a solvent and a base or an acid are added.

[0419] In certain embodiments, the solvent is a polar protic solvent such as methanol, ethanol, isopropanol or water, or a combination of at least one polar aprotic solvent with a polar aprotic solvent such as THF, dioxane, DME, disopropylether, ether diethyl, MTBE, CPME or toluene. In particular embodiments, the solvent is a combination of toluene, methanol and water.

[0420] In certain embodiments, the base is a hydroxide base such as lithium hydroxide, sodium hydroxide and potassium hydroxide or a silanolate base such as sodium trimethylsilanolate and potassium trimethylsilanolate. In particular embodiments, the base is lithium hydroxide.

[0421] In certain embodiments, the acid is a strong concentrated acid such as sulfuric acid and hydrochloric acid.

[0422] In certain embodiments, the reaction is stirred at about 0 to 80 ° C, about 5 to 70 ° C, about 10 to 60 ° C, about 15 to 50 ° C, about 20 to 40 ° C, about 25 to 30 ° C

[0423] In certain embodiments, the product formed is extracted and optionally purified by any suitable technique known in the art, such as, but not limited to, solvent extraction, chromatography, crystallization or a combination thereof.

[0424] In particular embodiments, toluene and 25% NaCl are added and the layers are separated. The organic layer is washed with a 20% NaCl solution adjusted to approximately pH 7 to approximately pH 8 with 1 N HCl. The organic layer is filtered and concentrated. Toluene is added and distillation is continued. Toluene and activated carbon are added. The mixture is heated to about 30 to about 40 ° C and stirred for about 2 to 6 h. The contents are cooled, filtered through celite and washed with toluene. The filtrate is concentrated. N-Heptane is added for about 1 to 2 hours and the mixture is optionally seeded with c-1 and stirred for an additional 2 to 3 hours. N-Heptane is added and the mixture is stirred for about 2 to 3 h. The mixture is cooled to about 10 to 15 ° C and stirred for an additional 3 to 5 h. The product is collected by filtration and washed with n-heptane at approximately 10 to 15 ° C. The product is dried to give c-1.

[0425] In particular embodiments, the PG protecting group is Boc, the solvent is a polar aprotic solvent, the oxidant is mCPBA, the reaction is stirred at 10 to 45 ° C, hydrolysis occurs in a combination of toluene, methanol and water at about 10 to 60 ° C, and the base is a hydroxide base.

[0426] In particular embodiments, the PG protecting group is Boc, the solvent is toluene, the oxidant is mCPBA, the reaction is stirred at 25 to 30 ° C, hydrolysis occurs in a combination of toluene, methanol and water at approximately 25 to 30 ° C, and the base is lithium hydroxide.

R. Resolution of c-1a - Selective acylation

[0427]

c-1a (+/-): racemic mixture of cc-1b and cc-1a.

[0428] In certain embodiments, enantium-enriched cc-1a is obtained through enzymatically catalyzed selective acylation.

[0429] In this process, the racemic starting material c-1a is a mixture of cc-1b and cc-1a (ie, c-1a (+/-) and is dissolved in a solvent.

[0430] In certain embodiments, the solvent is a polar aprotic solvent, a non-polar solvent, a polar protic solvent, a mixture of organic solvents with aqueous buffers or a mixture thereof. Examples of polar aprotic solvents include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, 2-methyltetrahydrofuran, tetrahydrofuran, dichloromethane and chloroform. Exemplary non-polar solvents include, among others, toluene, hexane and heptane. Exemplary polar protic solvents include, but are not limited to, tbutanol. In particular embodiments, the solvent used is toluene.

[0431] Once the racemic starting material C-1 a dissolves in the solvent, approximately 1 equivalent of an acyl donor is added. In certain embodiments, the acyl donor is an anhydride or an ester. In certain embodiments, the anhydride includes, among others, glutaric anhydride and acetic anhydride. In certain embodiments, the ester includes, but is not limited to, vinyl acetate, isopropenyl acetate, 4-chlorophenyl acetate and ethyl methoxy acetate. In particular embodiments, the acyl donor is glutaric anhydride.

[0432] In certain embodiments, R ^x is (C- ^i- C ⁶ ) -R ^y y R alkyl ^and is selected from the group consisting of H, CN, -NR ^z1 R ^z2 , C (O) R ^z1 , - C (O) OR ^z1 , -C (O) NR ^z1 R ^z2 , -OC (O) NR ^z1 R ^z2 , -NR ^z1 C (O) R ^z2 , -NR ^z1 C (O) NR ^z2 , -NR ^z1 C (O) OR ^z2 , -SR ^z1 , -S (O) ^1-2 R ^z1 , -S (O) ² NR ^z1 R ^{z 2} -NR ^z1 S (O) ² R ^z2 , NR ^z1 S (O) ² R ^z2 and OR ^z1 .

[0433] In certain embodiments, R ^z1 and R ^z2 are independently selected from the group consisting of H, C ^1-6 alkyl, C ^2-6 alkenyl, C ^2-6 alkynyl, heteroalkyl C ^1-6 cycloalkyl C ^{3- 10} , 3-12 membered heterocyclyl, heterocyclyl Ca-io and heteroaryl of 5 to 10 members.

[0434] In certain embodiments, Rx is alkyl (Ci-C4) -Ry and Ry is selected from the group consisting of H and CO2H.

[0435] In certain embodiments, Rx is methyl or (CH2) 3-CO2H. In certain embodiments, Rx is (CH2) 3-CO2H.

[0436] Approximately 15% by weight of an enzyme is added. In certain embodiments, the enzyme is a lipase. In certain embodiments, the lipase includes, among others, Novozyme 435, CAL-A, CAL-B, PPL, PSL-C, PSL, CRL and MML. In certain embodiments, the lipase includes but is not limited to CAL-A, CAL-B, PPL, PSL-C, PSL, CRL and MML. In particular embodiments, the enzyme used is Novozyme 435.

[0437] In certain embodiments, the reaction is allowed to stir for about 1 to 48 h for about 6 to 48 h, for about 12 to 30 h, for about 20 to 26 h, for about 23 h.

[0438] In certain embodiments, the reaction is allowed to stir at about 0 to 60 ° C at about 5 to 3 ° C, at about 10 to 15 ° C.

[0439] In certain embodiments, additional enzyme is added and the reaction is allowed to continue for about 1 to 48 h at about 0 to 60 ° C. In certain embodiments, about 5% by weight of additional enzyme is added and the reaction is allowed to proceed from about 6 to 24 hours at about 5 to 30 ° C. In particular embodiments, additional enzyme is added and the reaction is allowed to proceed for about 12 hours at about 10 to 15 ° C.

[0440] In certain embodiments, the ester formed E-1 is extracted and optionally purified by any suitable technique known in the art, such as, but not limited to, solvent extraction, chromatography, crystallization or a combination thereof.

[0441] In certain embodiments, precipitated enzyme solids are removed by filtration and rinsed with solvent. The desired e-1 is extracted in a basic aqueous layer such as aqueous Na2CO3. The aqueous solution is washed with an organic solvent (such as MTBE) to remove unwanted material. A solvent (such as THF) is then added to the aqueous layer, which contains E-1, followed by hydroxide.

[0442] In certain embodiments, the solvent is a polar aprotic solvent. Examples of polar aprotic solvents include, among others, diethyl ether, diisopropyl ether, methyl t-butyl ether, 2-methyltetrahydrofuran, tetrahydrofuran, dichloromethane and chloroform. In particular embodiments, the solvent is THF.

[0443] Exemplary sources of hydroxide include, but are not limited to, sodium hydroxide, potassium hydroxide and lithium hydroxide. In particular embodiments, the source of hydroxide is sodium hydroxide.

[0444] In certain embodiments, the mixture is allowed to stir for about 1 to 24 hours at about 0 to 60 ° C. In certain embodiments, the mixture is allowed to stir for about 1 to 12 h at about 5 to 30 ° C. In particular embodiments, the mixture is allowed to stir for about 4 hours at about 15 to 20 ° C.

[0445] In certain embodiments, the cc-1a product is extracted and optionally purified by any suitable technique known in the art, such as, but not limited to, solvent extraction, chromatography, crystallization or a combination thereof.

[0446] In particular embodiments, the layers are separated, and the organic layer is concentrated.

[0447] In certain embodiments, the organic phase is concentrated and cc-1a is recrystallized from a solvent with the addition of cc-1a seeds. In certain embodiments, the solvent is a mixture of THF, dichloromethane and water, and recrystallization is performed at about 40 to 50 ° C.

[0448] In certain embodiments, the enantiomeric excess (% ee) of the product is from about 50 to 100, about 75 to 100, about 90 to 100, about 95 to 100, about 98 to 100, about 98.5 to 100, about 98.5 at 99, about 99 to 100, about 99.5 to 100, about 99.9 to 100.

[0449] In particular embodiments, c-1a is dissolved in a non-polar solvent, the acyl donor is glutaric anhydride, Rx is (CH2) 3-CO2H, the enzyme used is a lipase, the reaction is stirred at about 10 to At 15 ° C, cc-1b is removed by filtration, hydrolysis occurs in THF at about 5 to 30 ° C, and the hydroxide source is sodium hydroxide.

[0450] In particular embodiments, c-1a is dissolved in toluene, the acyl donor is glutaric anhydride, Rx is (CH2) 3-CO2H, the enzyme used is Novozyme 435, the reaction is stirred at about 10 to 15 ° C, cc-1b is removed by filtration, hydrolysis occurs in THF at about 15 to 20 ° C, and the Source of hydroxide is sodium hydroxide.

S. Resolution of C-1a - Selective hydrolysis

[0451]

[0452] In certain embodiments, the enantium enriched cc-1a is obtained through enzymatically catalyzed selective hydrolysis.

[0453] A mixture of the starting material, c-1a, an acyl donor, a base and a catalyst in a solvent is stirred.

[0454] In certain embodiments, the acyl donor includes, but is not limited to, an anhydride or an acid chloride. In certain embodiments, the anhydride includes, among others, succinic anhydride and acetic anhydride. In certain embodiments, the acid chloride includes, among others, acetyl chloride and benzoyl chloride. In particular embodiments, the acyl donor is glutaric anhydride.

[0455] In certain embodiments, Rx is alkyl (Ci-C6) -Ry and Ry is selected from the group consisting of H, CN, -NRz1Rz2, C (O) Rz1, -C (O) ORz1, -C (O ) NRz1Rz2, -OC (O) NRz1Rz2, -NRz1C (O) Rz2, -NRz1C (O) NRz2, -NRz1C (O) ORz2, -SRz1, -S (O) 1-2Rz1, -S (O) 2NRz1Rz2- NRz1S (O) 2Rz2, NRz1S (O) 2Rz2 and ORz1.

[0456] In certain embodiments, Rz1 and Rz2 are independently selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycle, C6-10 aryl and 5-10 membered heteroaryl.

[0457] In certain embodiments, Rx is (C1-C4) alkyl -Ry and Ry is selected from the group consisting of H and CO2H.

[0458] In certain embodiments, Rx is methyl or (CH2) 3-CO2H. In certain embodiments, Rx is (CH2) 3-CO2H.

[0459] In certain embodiments, the catalyst includes, but is not limited to, compounds containing nucleophilic amines and compounds containing nucleophilic phosphine. In certain embodiments, compounds containing nucleophilic amines include, among others, imidazole, 4-dimethylaminopyridine derivatives, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] undec-7-eno , and pyridine. In certain embodiments, nucleophilic phosphine-containing compounds include, but are not limited to, triphenylphosphine. In particular embodiments, the catalyst is 4-dimethylaminopyradine.

[0460] In certain embodiments, the base includes, but is not limited to, amine bases, aromatic amine bases, inorganic carbonates, metal hydrides and alkoxides. In certain embodiments, the amine bases include, but are not limited to, W, W-diisopropylethylamine, quinuclidine, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] undec-7- eno, tripropylamine, and tributylamine. In certain embodiments, the bases of aromatic amines include, but are not limited to pyridine. In certain embodiments, inorganic carbonate bases include, among others, lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate. In certain embodiments, metal hydride bases include, but are not limited to, sodium hydride and potassium hydride. In certain embodiments, the alkoxide bases include, but are not limited to, sodium methoxide, sodium ferc-butoxide and lithium ferc-butoxide. In particular embodiments, the base is pyridine.

[0461] In certain embodiments, the solvent is an aromatic solvent or a non-protic polar solvent. In certain embodiments, the aromatic solvent includes, but is not limited to, pyridine, toluene, xylene, benzene and chlorobenzene. In certain embodiments, the non-protic polar solvent includes, but is not limited to, N, N-dimethylformamide, N, N- dimethylacetamide, 1,4-dioxane, N-methyl-2-pyrrolidinone and dichloromethane. In particular embodiments, the solvent is pyridine.

[0462] In certain embodiments, the reaction mixture is stirred for about 1 to 48 h, for about 6 to 24 h, for about 12 h.

[0463] In certain embodiments, the reaction mixture is stirred at about 0 to 120 ° C, about 20 to 100 ° C, about 40 ° C to 80 ° C, or about 60 ° C.

[0464] In certain embodiments, the ee-1 product is extracted and optionally purified by any suitable technique known in the art, such as, among others, solvent extraction, chromatography, crystallization or a combination thereof.

[0465] In particular embodiments, the reaction mixture is evaporated to dryness, dissolved in DCM and washed with an aqueous solution of 0.2 M HCl. The organic layer evaporates to dryness. The residue is stirred with water and the pH is adjusted to approximately 7.8 with a 2M solution of NaOH. The water layer is washed with DCM. The aqueous layer is then acidified to pH 4 with 3 N HCl aqueous solution and DCM is extracted. The combined organic layers are dried over Na2SO4, filtered and evaporated. Crushing with pentane, followed by filtration and vacuum drying, produces ee-1.

[0466] ee-1 is suspended in a solvent, an enzyme is added.

[0467] In certain embodiments, the solvent is a polar aprotic solvent, a non-polar solvent or a mixture of organic solvents with aqueous buffers. In certain embodiments, the polar aprotic solvent includes, among others, diethyl ether, diisopropyl ether, methyl t-butyl ether, 2-methyltetrahydrofuran, tetrahydrofuran, dichloromethane and chloroform. In certain embodiments, non-polar solvents include, among others, hexane and heptane. In particular embodiments, the solvent is diisopropyl ether: phosphate buffer 1: 2.

[0468] In certain embodiments, the enzyme is a lipase such as, among others, CAL-A, CAL-B, PPL, PSL-C, PSL, CRL and MML. In particular embodiments, the enzyme is CAL-B.

[0469] In certain embodiments, the reaction is stirred at 0 to 60 ° C, 10 to 50 ° C, 20 to 40 ° C, at approximately 30 ° C.

[0470] In certain embodiments, the reaction is stirred for 24 to 200 hours, 50 to 150 hours, approximately 100 hours.

[0471] In certain embodiments, the cc-1a product is extracted and optionally purified by any suitable technique known in the art, such as, but not limited to, solvent extraction, chromatography, crystallization or a combination thereof.

[0472] In certain embodiments, e-2 is removed by extraction with an aqueous layer. In certain embodiments, the e-2 product is removed by extraction in a basic aqueous layer.

[0473] In particular embodiments, the reaction mixture is filtered and the layers of the filtrate are separated. The solid is washed with DCM and the filtrate is used to extract the aqueous layer. The combined organic layers are washed with 5% Na2CO3, brine and dried. Filtration and evaporation of volatile compounds under reduced pressure produces cc-1a.

[0474] In particular embodiments, the acyl donor is an anhydride, Rx is alkyl (Ci-C4) -Ry 'Ry is selected from the group consisting of H and CO2H, the catalyst is 4-dimethylaminopyridine, the basis for the first stage is pyridine, the solvent for the first stage is an aromatic solvent, the reaction mixture in the first stage is stirred at about 0 to about 60 ° C, the solvent for hydrolysis is diisopropyl ether: phosphate buffer 1: 2, the enzyme is CAL-B, and the hydrolysis reaction is stirred at about 0 to about 30 ° C.

[0475] In particular embodiments, the acyl donor is glutaric anhydride, Rx is (CH2) 3-CO2H, the catalyst is 4-dimethyl-aminopyridine, the base for the first stage is pyridine, the solvent for the first stage is pyridine , The reaction mixture in the first stage is stirred at approximately 60 ° C, the solvent for hydrolysis is diisopropyl ether: phosphate buffer 1: 2, the enzyme is CAL-B, the hydrolysis reaction is stirred at approximately 30 ° C , and -2 is removed by extraction in a basic aqueous layer.

[0476] In certain embodiments, the enantiomeric excess (% ee) of the product is about 50 to 100, about 75 to 100, about 90 to 100, about 95 to 100, about 98 to 100, about 98.5 to 100, about 98.5 to 99, approximately 99 to 100, approximately 99.5 to 100, approximately 99.9 to 100.

T. Classic resolution of c-1a

[0477]

c-ii

[0478] In certain embodiments, c-1a is resolved through a classic resolution process. In this process, c-1a, an acid and a solvent are combined.

[0479] In certain embodiments, the acid is selected from the group consisting of:

- individual enantiomers of carboxylic acids, including but not limited to naproxen, phenylsuccinic acid, malic acid, 2-phenylpropionic acid, alpha-methoxy-phenyl-acetic acid, tartranilic acid, 3-phenylactic acid, a-hydroxyisovaleric acid, 2 ' -methoxytartranilic, phthalic (alpha-methylbenzyl) acid, 2'-chlorotartranilic acid, pyroglutamic acid;

- individual enantiomers of derivatives of mandelic acid which include, among others: mandelic acid, 2-chloromelic acid, 4-bromo-mandelic acid, O-acetyl mandelic acid, 4-methyl-mandelic acid;

- individual enantiomers of sulfonic acids that include, among others: camphor sulfulfic acid;

- individual enantiomers of derivatives of tartaric acid, including but not limited to: tartaric acid, dibenzoyl-tartaric acid hydrate, di-p-anisoyltartaric acid, di-toluyltartaric acid, dibenzoylotartaric acid hydrate;

- individual enantiomers of phosphoric acid derivatives, which include, but are not limited to: hydrophilic phenyl, clocifos, anisiphos, BINAP phosphate; Y

- individual enantiomers of amino acids that include, among others, the following: N-acetyl-phenylalanine, N- acetyl-leucine, N-acetyl-proline, boc-phenylalanine and boc-homophenylalanine.

[0480] In some embodiments, the acid is (S) -aproxen or S - (+) - mandelic acid. In particular embodiments, the acid is (S) -aproxen. In particular embodiments, the acid is S - (+) - mandelic acid.

[0481] In certain embodiments, the solvent is water, acetonitrile, ethanol, isopropanol, ethyl methyl ketone, isopropyl acetate, dioxane, a mixture of water and water-miscible organic solvents such as ethanol and isopropanol, a halogenated solvent such as dichloromethane and chloroform. In particular embodiments, the solvent is water or isopropanol or a mixture thereof. In particular embodiments, the solvent is water. In particular embodiments, the solvent is isopropanol.

[0482] In certain embodiments, the reaction is stirred at 0 to 120 ° C, 2 to 120 ° C, 50 to 120 ° C, 80 to 120 ° C, approximately 100 ° C. In certain embodiments, the reaction is stirred at approximately 20 ° C.

[0483] In certain embodiments, the product is extracted and optionally purified by any suitable technique known in the art, such as, but not limited to, solvent extraction, chromatography, crystallization or a combination thereof.

[0484] In certain embodiments, dd-1 is precipitated from the solution and filtered. The solid can be further recrystallized from a solvent such as isopropanol.

[0485] In particular embodiments, solvent removal by evaporation produces a mixture of dd-1 and dd-2. The mixture is suspended in a solvent.

[0486] In certain embodiments, dd-1 is selectively recrystallized.

[0487] In certain embodiments, the solvent is water, acetonitrile, ethanol, isopropanol, ethyl methyl ketone, isopropyl acetate, dioxane; a mixture of water and water-miscible organic solvents, such as ethanol and isopropanol, or a halogenated solvent, such as dichloromethane or chloroform. In particular embodiments, the solvent is a mixture of ethyl methyl ketone and water.

[0488] In certain embodiments, the mixture is stirred at about 0 to 100 ° C, about 20 to 80 ° C, about 40 to 60 ° C.

[0489] In certain embodiments, the mixture is allowed to cool to room temperature and the solid is isolated by filtration, dried and recrystallized from 10% water in methyl ethyl ketone to provide enantium enriched dd-1.

[0490] In particular embodiments, the acid is S - (+) - mandelic acid or (S) -aproxen, the solvent is water or isopropanol, the reaction is stirred at about 0 to about 20 ° C, and dd-1. The product is isolated by solvent extraction, chromatography, crystallization or a combination thereof.

[0491] In particular embodiments, the acid is S - (+) - mandelic acid, the solvent is isopropanol, the reaction is stirred at about 20 ° C, and dd-1 is precipitated from the solution.

[0492] In particular embodiments, the acid is the acid is (S) -Naproxen, the solvent is water, the reaction is stirred at about 20 ° C and dd-1 is selectively recrystallized from a mixture of ethyl ketone and water. .

[0493] In certain embodiments, the enantiomeric excess (% ee) of the product is about 50 to 100, about 75 to 100, about 90 to 100, about 95 to 100, about 98 to 100, about 98.5 to 100, about 98.5 to 99, approximately 99 to 100, approximately 99.5 to 100, approximately 99.9 to 100.

U. Allylic Amination

[0494]

[0495] In certain embodiments, an allylic amination process for obtaining g-1x is provided. In this process, a ligand and a catalyst are mixed in a degassed solvent, followed by the off-1x addition, a base and a nucleophile.

[0496] In certain embodiments, the ligand is absent, tricyclohexylphosphine, 1,3-bis (diphenylphosphino) propane; 1,2-bis (diphenylphosphine) ethane, triphenylphosphine or 1,1'-bis (diphenylphosphino) ferrocene. In particular embodiments, the ligand is triphenylphosphine.

[0497] In certain embodiments, the catalyst is a palladium catalyst such as Pd (OAc) ² , PdCl ² (PPh ³ ), Pd (tBu ² Ph) ² Cl ² , Tris (dibenzylidenacetone) dipaladium (0) and Pd ( amps) ² Ch. In particular embodiments, the catalyst is Tris (dibenzidenoketone) dipaladium (0).

[0498] In certain embodiments, the solvent is an ether such as dimethoxyethane, THF or MeTHF, an aromatic solvent such as toluene and benzene. In particular embodiments, the solvent is THF.

[0499] In certain embodiments, the base is potassium isopropoxide, cesium hydroxide, Hunig base or a carbonate base such as cesium carbonate, potassium carbonate and sodium carbonate. In particular embodiments, the base is cesium carbonate.

[0500] In certain embodiments, the nucleophile is a phthalamide such as potassium phthalamide, an azide such as sodium azide or TMS-azide, an amine such as benzylamine or dibenzylamine, a carboxylate such as di-ferc-butyl. In particular embodiments, the nucleophile is di-ferc-butyl iminodicarboxylate.

[0501] In certain embodiments, approximately 1 nucleophile equivalent is added.

[0502] In certain embodiments, the reaction is stirred at about 20 to 80 ° C, about 30 to 70 ° C, about 40 to 60 ° C, about 50 ° C.

[0503] In certain embodiments, the mixture is heated at about 50 ° C for about 18 h.

[0504] In certain embodiments, the product formed is extracted and optionally purified by any suitable technique known in the art, such as, but not limited to, solvent extraction, chromatography, crystallization or a combination thereof.

[0505] In certain embodiments, the mixture is cooled and water and ethyl acetate are added. The layers are separated and the organic phase is washed with ethyl acetate. The combined organic compounds are concentrated to dryness. The residue is purified by silica gel column chromatography (0 to 40% ethyl acetate in hexane). The isolated material is dissolved in MeTHF, washed with 5% aq. KOH, concentrated and purified by silica gel column chromatography (0 to 10% methanol in dichloromethane) to provide g-1x.

[0506] In particular embodiments, the ligand is triphenylphosphine, the catalyst is a palladium catalyst, the solvent is an ether, the base is a carbonate base, the nucleophile is di-ferc-butyl iminodicarboxylate and the reaction is stirred at approximately 20 at about 80 ° C.

[0507] In particular embodiments, the ligand is triphenylphosphine, the catalyst is Tris (dibenzylidene ketone) dipaladium (0), the solvent is THF, the base is cesium carbonate, the nucleophile is di-ferc-butyl iminodicarboxylate and the reaction is stir at about 50 ° C.

V. Hydrogenation

[0508]

[0509] In certain embodiments, a hydrogenation process is provided to obtain h-1x. In this process, g-1x and a catalyst are combined in a solvent, followed by the addition of a hydrogen source.

[0510] In certain embodiments, the catalyst is a platinum catalyst such as PtO ² , a palladium catalyst, a nickel catalyst such as Raney nickel, a rhodium catalyst such as RhCl (PPh ³ ) ³ , a ruthenium catalyst such as Nyori catalyst, or an iridium catalyst such as the Crabtree catalyst. In some embodiments, the catalyst is selected from the group consisting of Pd / C, PtO ² , Raney nickel, RhCl (PPh ³ ) ³ , Nyori catalyst and Crabtree catalyst. In particular embodiments, the catalyst is PtO ² .

[0511] In certain embodiments, the solvent is a polar aprotic solvent such as THF, 2-MeTHF, dioxane, diethyl ether, diisopropyl ether, DME, MTBE, CPME, EtOAc and DCM or a polar protic solvent such as methanol, isopropanol. ethanol, and n-butanol. In particular embodiments, the solvent is isopropanol.

[0512] In certain embodiments, the reaction is stirred at about 0 to 65 ° C, about 5 to 55 ° C, about 10 to 45 ° C, about 10 to 35 ° C, or about 15 to 25 ° C

[0513] In certain embodiments, the source of hydrogen is formic acid, hydrazine, dihydronaphthalene, dihydroanthramene, H ² gas or Hantzch ester and isopropanol. In particular embodiments, the source of hydrogen is H ² gas. In particular embodiments, the source of hydrogen is an atmosphere of hydrogen.

[0514] In certain embodiments, the reaction is stirred for 1 to 48 h, 6 to 24 h, 10 to 20 h, 16 to 20 h, or about 18 h.

[0515] In certain embodiments, h-1x is extracted and optionally purified by any suitable technique known in the art, such as, but not limited to solvent extraction, chromatography, crystallization or a combination thereof.

[0516] In certain embodiments, the mixture is filtered through celite and used without further purification in subsequent deprotection.

[0517] In particular embodiments, the catalyst is a platinum catalyst, the solvent is a polar protic solvent, the reaction is stirred at about 5 to 55 ° C, and the source of hydrogen is H ² gas.

[0518] In particular embodiments, the catalyst is PtO ² , the solvent is isopropanol, the reaction is stirred at about 15 to 25 ° C and the source of hydrogen is H ² gas.

W. Check out

[0519]

[0520] In certain embodiments, a deprotection process is provided to obtain N-1x. In this process, h-1x is added to an acid in a solvent.

[0521] In certain embodiments, the acid is a sulfonic acid such as methanesulfonic acid, ptoluenesulfonic acid and camphorsulfonic acid, an inorganic acid such as phosphoric acid, hydrochloric acid and sulfuric acid, a carboxylic acid such as trifluoroacetic acid, oxalic acid and acid. benzoic. In particular embodiments, the acid is anhydrous hydrochloric acid.

[0522] In certain embodiments, the solvent is an alcoholic solvent such as methanol, isopropanol and ethanol, or a polar aprotic solvent such as dioxane, acetonitrile and dichloromethane, or water. In certain embodiments, the solvent is an alcoholic solvent. In certain embodiments, the solvent is a polar aprotic solvent. In certain embodiments, the solvent is water. In certain embodiments, the solvent is methanol, isopropanol, ethanol, dioxane, acetonitrile, dichloromethane or water. In particular embodiments, the solvent is isopropanol.

[0523] In certain embodiments, the reaction is stirred at about 0 to 80 ° C, about 0 to 60 ° C, about 5 to 45 ° C, about 10 to 35 ° C, or about 15 to 25 ° C.

[0524] In certain embodiments, about 1 to 10 equivalents, about 5 to 10 equivalents, or about 7 equivalents of acid are used.

[0525] In certain embodiments, the reaction is stirred for about 1 to 48 h, about 6 to 24 h, about 12 to 24 h, or about 18 h.

[0526] In certain embodiments, the formed product, N-1x, is extracted and optionally purified by any suitable technique known in the art, such as, but not limited to, solvent extraction, chromatography, crystallization or a combination thereof. . In particular embodiments, the reaction is cooled to about 0 ° C and the N-1x product is collected by filtration.

[0528] In particular embodiments, the acid is an inorganic acid, the solvent is an alcoholic solvent and the reaction is stirred at a temperature of 5 to 45 ° C.

[0529] In particular embodiments, the acid is anhydrous hydrochloric acid, the solvent is isopropanol and the reaction is stirred at a temperature of 15 to 25 ° C.

EXAMPLES

[0530] For this invention to be more fully understood, the following examples are set forth. These examples are intended to illustrate embodiments, and should not be construed as limiting the scope of this description in any way. The reagents used in the following examples can be obtained as described herein, or if not described herein, are commercially available or can be prepared from commercially available materials by methods known in the art.

[0531] In one embodiment, a multi-step synthetic method is provided for preparing a compound of Formula I, as set forth below. In certain embodiments, each of the individual steps of the Schemes set forth below is provided. Examples and any combination of two or more successive steps of the following examples are provided.

A. Acylation and amidation of Meldrum acid to form C-1a:

[0532]

[0533] In a reaction vessel, Meldrum acid (101 g, 1.0 equivalent) and 4-dimethylaminopyridine (1.8 g, 0.2 equivalent) were combined with acetonitrile (300 ml). The resulting solution was treated with methoxyacetic acid (6.2 ml, 1.2 equivalents). Triethylamine (19.4 ml, 2.0 equivalents) was added slowly to the resulting solution, followed by pivaloyl chloride (9.4 ml, 1.1 equivalents). The reaction was then heated to about 45 to about 50 ° C and aged until the consumption of Meldrum acid was considered complete.

[0534] A separate reaction vessel was charged with acetonitrile (50 ml) and J-1a (13.4 g, 1.2 equivalents). The resulting solution was treated with trifluoroacetic acid (8.0 ml, 1.5 equivalents), and then this acid solution was added to the acylation reaction in progress at about 45 to about 50 ° C.

[0535] The reaction was allowed to age for at least 18 hours at about 45 to about 50 ° C, after which the solvent was removed under reduced pressure. The crude residue was dissolved in ethyl acetate (150 ml) and the organic layer was washed with water. The combined aqueous layers were extracted with ethyl acetate. The combined organic layers were washed with a saturated sodium bicarbonate solution and the combined bicarbonate washes were extracted again with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting crude material was purified twice by silica gel chromatography to produce c-1a.

[0536] ¹ H NMR (400 MHz, CDCl ^a ): 87.12 (br, 1H), 6.66 (ap t, J = 8.1 Hz, 2H), 4.50 (ap d, J = 5 , 7 Hz, 2H), 4.08 (s, 2H), 3.44 (s, 2H), 3.40 (s, 3H). ¹³ C NMR (100 MHz, CDCl ^a ): 8203.96, 164.90, 162.37 (ddd, J = 250.0, 15.7, 15.7 Hz), 161.71 (ddd, J = 250 , 3, 14.9, 10.9 Hz), 110.05 (ddd, J = 19.7, 19.7, 4.7 Hz), 100.42 (m), 77.58, 59.41, 45.71, 31.17 (t, J = 3.5 Hz). LCMS, calculated: 275.23, found: 275.97 (M).

B. Alkylation of c-1a to form E-1a:

[0537]

[0538] A solution of C-1a (248 mg, 1.0 equivalent) and 2-methyl tetrahydrofuran (1.3 ml) was treated with N, N- dimethylformamide dimethylacetal (0.1 ml, 1.1 equivalent) and stirred at room temperature overnight (~ 14 hours). The reaction was treated with acetal aminoacetaldehyde dimethyl (0.1 ml, 1.0 equivalent) and allowed to age for about 2 hours and then stopped by the addition of 2 N HCl (1.5 ml).

[0539] The reaction was diluted by the addition of ethyl acetate and the phases were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to give E-1a.

[0540] 1H NMR (400 MHz, CDCh): 810.85 (s, 1H), 9.86 (s, 1H), 8.02 (d, J = 13.1 Hz, 1H), 6.65 ( dd, J = 8.7, 7.7 Hz, 2H), 4.53 (d, J = 3.9 Hz, 2H), 4.40 (t, J = 5.1 Hz, 1H), 4, 18 (s, 2H), 3.42 (s, 6H), 3.39 (m, 2H), 3.37 (s, 3H). 13C NMR (100 MHz, CDCh): 8193.30, 169.15, 162.10 (ddd, J = 248.9, 15.5, 15.5 Hz), 161.7 (ddd, J = 250.0 , 14.9, 11.1 Hz), 161.66, 111.08 (ddd J = 19.9, 19.9, 4.7 Hz) 103.12, 100.29 (ddd, J = 28.1 , 17.7, 2.3 Hz), 76.30, 58.83, 54.98, 53.53, 51.57, 29.89 (t, J = 3.3 Hz). LCMS, calculated: 390.36, found: 390.92 (M).

C. Cyclization of E-1a to form F-1a:

[0541]

[0542] E-1a (0.2 g, 1.0 equivalent), dimethyl oxalate (0.1 g, 2.5 equivalents) and methanol (1.5 ml) were combined and cooled to about 0 to about 5 ° C Sodium methoxide (0.2 ml, 30% solution in methanol, 1.75 equivalents) was introduced slowly while maintaining the internal temperature of the reaction below about 10 ° C throughout the addition. After the addition was completed, the reaction was heated at about 40 to about 50 ° C for at least 18 hours.

[0543] After this time, the reaction was diluted with 2 N HCl (1.5 ml) and ethyl acetate (2 ml). The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure. The resulting crude oil was purified by silica gel chromatography to provide F-1a.

[0544] ¹ H NMR (400 MHz, CDCh): 810.28 (t, J = 5.5 Hz, 1H), 8.38 (s, 1H), 6.66-6.53 (m, 2H) , 4.58 (d, J = 5.6 Hz, 2H), 4.43 (t, J = 4.7 Hz, 1H), 4.00 (d, J = 4.7 Hz, 2H), 3 , 92 (s, 3H), 3.88 (s, 3H), 3.32 (s, 6H). ¹³ C NMR (100 MHz, CDCl ^a ): 8 173.08, 163.81, 162.17, 162.14 (ddd, J = 249.2, 15.6, 15.6 Hz), 161.72 ( ddd, J = 250.5, 15.0, 10.9 Hz), 149.37, 144.64, 134.98, 119.21, 110.53 (ddd, J = 19.8, 4.7, 4.7 Hz), 102.70, 100.22 (m), 60.68, 56.75, 55.61, 53.35, 30.64. LCMS, calculated: 458.39, found: 459.15 (M + H).

D. Alkylation and cyclization of c-1a to form F-1a:

[0545]

[0546] C-1a (245 mg, 1.0 equivalent) and W, W-dimethylformamide dimethylacetal (0.5 ml, 4.3 equivalent) were added to a reaction vessel. The reaction mixture was stirred for approximately 30 minutes. The reaction was then treated with 2-methyl tetrahydrofuran (2.0 ml) and amino acetaldehyde dimethyl acetal (0.1 ml, 1.0 equivalent). The reaction was allowed to age for several hours and then the solvent was removed under reduced pressure.

[0547] The resulting material was dissolved in methanol and dimethyl oxalate (0.3 g, 2.5 equivalents) was added. The reaction mixture was cooled to about 0 to about 5 ° C, and then sodium methoxide (0.4 ml, 30% solution in methanol, 1.75 equivalents) was introduced slowly into the reaction. After the addition was completed, the reaction was heated to about 40 to about 50 ° C.

[0548] After this time had elapsed, the reaction was cooled to room temperature and stopped by the addition of 2 N HCl (1.5 ml). The reaction was then diluted with ethyl acetate and the resulting phases were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to give F-1a.

[0549] 1H NMR (400 MHz, CDCh): 810.28 (t, J = 5.5 Hz, 1H), 8.38 (s, 1H), 6.66-6.53 (m, 2H), 4.58 (d, J = 5.6 Hz, 2H), 4.43 (t, J = 4.7 Hz, 1H), 4.00 (d, J = 4.7 Hz, 2H), 3, 92 (s, 3H), 3.88 (s, 3H), 3.32 (s, 6H). 13C NMR (100 MHz, CDCh): 8 173.08, 163.81, 162.17, 162.14 (ddd, J = 249.2, 15.6, 15.6 Hz), 161.72 (ddd, J = 250.5, 15.0, 10.9 Hz), 149.37, 144.64, 134.98, 119.21, 110.53 (ddd, J = 19.8, 4.7, 4, 7 Hz), 102.70, 100.22 (m), 60.68, 56.75, 55.61, 53.35, 30.64. LCMS, calculated: 458.39, found: 459.15 (M + H).

E. Condensation of F-la with N-1a to form G-1a:

[0550]

[0551] F-1a (202 mg, 1.0 equivalent) and acetonitrile (1.4 mL) were added to a reaction vessel. The resulting solution was treated with glacial acetic acid (0.2 ml, 6.0 equivalents) and methanesulfonic acid (0.01 ml, 0.3 equivalents). The reaction was then heated to about 70 to about 75 ° C.

[0552] After 3 hours, a solid mixture of N-1a (0.128 g, 1.5 equivalents) and potassium carbonate (0.2 g, 2.7 equivalents) was introduced to the reaction at about 70 to about 75 ° C. Once the addition was complete, the reaction was allowed to progress for at least about 1 hour.

[0553] After this time, water (1.4 ml) and dichloromethane (1.4 ml) were introduced into the reaction. The phases were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, then filtered and concentrated under reduced pressure. The resulting crude material was purified by silica gel chromatography to obtain G-la.

[0554] ¹ H NMR (400 MHz, CDCl ^a ): 810.23 (t, J = 5.5 Hz, 1H), 8.39 (s, 1H), 6.60 (t, J = 8.1 Hz, 2H), 5.29 (dd, J = 9.5, 3.7 Hz, 2H), 4.57 (d, J = 5.4 Hz, 3H), 4.33 (dd, J = 12 , 8, 3.8 Hz, 1H), 4.02-3.87 (m, 1H), 3.94 (s, 3H), 2.06-1.88 (m, 4H), 1.78 ( dd, J = 17.2, 7.5 Hz, 1H), 1.55-1.46 (m, 1H). ¹³ C NMR (100 MHz, CDCl ^a ): 8174.53, 163.75, 162.33 (dd, J = 249.4, 15.7, 15.7 Hz), 161.86 (ddd, J = 250 , 4, 14.9, 10.9 Hz), 154.18, 154.15, 142.44, 129.75118.88, 110.58 (ddd, J = 19.8, 4.7, 4.7 Hz), 100.42 (m), 77.64, 74.40, 61.23, 54.79, 51.13, 38.31, 30.73, 29.55, 28.04. LCMS, calculated: 463.14, found: 464.15 (M + H).

F. Deprotection of G-1a to form a compound of Formula la:

[0555]

[0556] G-1a (14 g) was suspended in acetonitrile (150 ml) and dichloromethane (150 ml). MgBr2 (12 g) was added. The reaction was heated at 40 to 50 ° C for approximately 10 minutes before cooling to room temperature. The reaction was poured into 0.5 M HCl (140 ml) and the layers separated. The organic layer was washed with water (70 ml) and the organic layer was concentrated. The crude product was purified by silica gel chromatography (100% dichloromethane to 6% ethanol / dichloromethane) to provide the.

G. Hydrolysis of F-1a to form ll-a:

[0557]

[0558] F-la (480 mg, 1.0 equiv.), Methanol (5.8 ml) and water (2.4 ml) were added to a reaction vessel. To the resulting homogeneous solution, lithium hydroxide monohydrate (88 mg, 2.0 equiv.) Is added. The resulting suspension was stirred at room temperature for approximately 17 hours.

[0559] Water (15 ml) and ethyl acetate were added, then 1 N HCl was added dropwise until the pH was approximately 3. The layers were mixed and separated, the aqueous layer was extracted with ethyl acetate ( 15 ml) and the combined organic mixture. The layers were dried over Na ² SO ⁴ . The organic layer was removed by evaporation. The aqueous layer was then brought to pH <2 and extracted twice with ethyl acetate (2 x 15 ml). The combined organic layers were dried over Na ² SO ⁴ , mixed with the residue from the previous extraction and the solvent was removed by evaporation. The residue was taken up in MTBE (2.4 ml), to form a suspension, which was filtered and washed with MTBE to provide 1002.

[0560] ¹ H NMR (400 MHz, CDCl ^s ): 810.43 (t, J = 5.2 Hz, 1H), 9.65 (bs, 1H), 8.52 (s, 1H), 6, 67 (t, J = 8.0 Hz, 2H), 4.67 (d, J = 6.0 Hz, 2H), 4.58 (t, J = 4.8 Hz, 1H), 4.16 ( d, J = 4.8 Hz, 1H), 3.91 (s, 3H), 3.37 (s, 6H). ¹³ C NMR (100 MHz, CDCl ^a ): 8 173.04, 164.15, 162.10, 148.63, 145.28, 137.25, 118.66, 102.46, 100.35 (t, J = 30.7 Hz), 87.42, 61.30, 57.09, 55.55, 30.94.

H. Preparation of BB-1a from B-1a:

[0561]

[0562] B-1a (0.2 g, 1.0 equivalent) and 3-pentanone (1.0 mL, 10.0 equivalents) were added to a reaction vessel. These compounds were then dissolved in toluene (1.0 ml) and heated to about 110 to about 115 ° C. The reaction was maintained at this temperature for approximately 4 hours, after which the reaction was cooled to room temperature and the solvent was removed. The resulting crude material was purified on silica gel to provide BB-1a.

[0563] 1H NMR (400 MHz, CDCh): 85.46 (t, J = 1.1 Hz, 1H), 3.97 (d, J = 1.0 Hz, 2H), 3.42 (s, 3H), 1.99 (m, 4H), 0.98 (t, J = 7.5 Hz, 6H). 13C NMR (100 MHz, CDCh): 8167.63, 160.94, 111.05, 93.04, 70.07, 59.27, 28.08, 7.40, LCMS, calculated: 200.10, found 200.79 (M +).

I. Preparation of C-1a from BB-1a:

[0564]

[0565] BB-1a (0.08 g, 1.0 equivalent) and N-1a (0.08 g, 1.1 equivalents) were added to a reaction vessel. These compounds were then dissolved in toluene (1.5 ml) and heated to approximately 115 ° C. After about 1 h, the reaction was cooled and the solvent was removed. The resulting crude material was purified by silica gel chromatography to obtain C-1a.

[0566] All spectral data collected for C-1a matches those provided above.

J. Salt formation B-1aJ-1a:

[0567]

[0568] B-1a free acid (4.4 g) was dissolved in 50 ml of acetonitrile and J-1a (3.3 g, 1.0 equivalent) in 30 ml of acetonitrile was added. The desired salt was obtained and aged for approximately one hour at room temperature. The solids were filtered and the cake was rinsed with 2 x 10 ml of acetonitrile to provide the product.

[0569] ¹ H NMR (400 MHz, DMSO-d ^a ) 87.40 (bs, 3H), 6.11 (t, J = 7.7 Hz, 2H), 3.12 (s, 2H), 2 , 92 (s, 2H), 2.08 (s, 3H), 0.35 (s, 6H). ¹³ C NMR (101 MHz, DMSO-d ^a ) 8 191.98, 164.66, 163.06 (dt, J = 248.6, 16.2 Hz), 161.82 (ddd, J = 250.4 , 15.8, 10.4 Hz), 107.39 (td, J = 20.0, 4.7 Hz), 101.16 (m), 100.01, 87.01, 77.71, 58, 39, 30.45, 26.37.

K. Salt formation B-1aJ-1a:

[0570]

[0571] Meldrum acid (10.1 g, 1.1 equivalents) and DMAP (0.6 g, 0.08 equivalents) were dissolved in 300 ml of acetonitrile. Methoxyacetic acid (5.8 g, 1 equivalent) and 17.6 g (2.1 equivalents) of Hunig base were added. The solution was heated to approximately 45 ° C and 8.4 g (1.1 equivalents) of pivaloyl chloride in 30 ml of acetonitrile was added for approximately 1 hour.

[0572] After about 2.5 hours at about 45 ° C, the solution was cooled to room temperature and concentrated in vacuo. The resulting oil was dissolved in 110 ml of dichloromethane, cooled on an ice bath and extracted with 50 ml of IN HCl. The layers were separated and the aqueous layer was extracted with 40 ml of dichloromethane. The combined organic layer was concentrated and diluted in acetonitrile and evaporated again. The material was dissolved in 220 ml of acetonitrile.

[0573] After cooling in an ice bath, trifluorobenzylamine (11.4 g, 1.1 equivalents) and the mixture at about 9 ° C were allowed to warm to room temperature and stir as the suspension became thick. After about 2 hours, 220 ml of MTBE was taken slowly added and the suspension was aged overnight. The suspension was cooled on an ice bath for approximately 3 hours and filtered, rinsed with 50 ml of cold 1: 1 acetonitrile / MTBE and dried overnight in a vacuum oven to provide the product.

L. Amidation using salt B-1aJ-1a to form c-1a

[0574]

[0575] Salt B-1aJ-1a (3.7 g, 1.0 equivalent) was suspended in 50 ml of acetonitrile and then treated with acid trifluoroacetic acid (0.1 ml, 0.1 equivalent). The reaction was heated at about 40 to about 50 ° C for about 18 hours, and then cooled to room temperature. The solvent was removed under reduced pressure and the resulting residue was suspended in 5 volumes of 2-methyl tetrahydrofuran and 5 volumes of hexanes were added dropwise over 1 h. The resulting mixture was allowed to stir for at least 24 hours and then the resulting suspension was filtered to provide the product.

M. Amidation of B-1a.J-1a to C-1a:

[0576]

[0577] B-1a.J-1a (75.077 g, 198.97 mmol, 1.0 equivalent), acetonitrile (750 mL) and trifluoroacetic acid (1.5 mL, 20 mmol, 0.1 equiv.) Were combined in a reactor The reactor was heated until the internal temperature reached approximately 58 ° C, and the reactor contents were aged between approximately 58-61 ° C for approximately 3.5 hours. The wrapping temperature was then adjusted to approximately 45 ° C and vacuum was applied. The reactor contents were distilled until approximately 150 ml remained. Isopropylacetate (300 ml) was then loaded into the reactor and distillation was continued until the volume reached approximately 150 ml. Then, isopropylacetate (150 ml) was charged to the reactor, the envelope temperature was adjusted to approximately 20 ° C and the content was allowed to reach an internal temperature of <25 ° C. A wash solution (22.8% NaCl, 1.5% H ² SO ⁴ , 75.7% water, 300 ml) was charged into the reactor and the content was stirred for approximately 30 minutes. The lower phase was separated and a second wash solution was loaded into the reactor (22.8% NaCl, 1.5% H ² SO ⁴ , 75.7% water, 300 ml). After stirring for approximately 15 minutes, the lower phase was separated and 20% aqueous NaCl (300 ml) was loaded into the reactor and stirred for approximately 15 minutes. The lower phase was separated. Heptane (150 ml) was loaded into the reactor, followed by seed (51 mg, 0.1% by weight). The mixture was aged for approximately 30 minutes, during which a suspension formed. Then additional heptane (450 ml) was charged for not less than 30 minutes. The temperature of the wrapper was adjusted to approximately 29 ° C and the solvent was distilled under vacuum until the reactor content reached a volume of approximately 450 ml. The suspension was then cooled to an internal temperature of about 5 ° C for not less than 1 hour. The reactor contents were discharged and the solids collected by filtration. The mother liquors were recycled twice to displace the solids from the reactor, each time allowing the internal temperature to reach approximately <6 ° C before discharge. Then a solution of heptane / iso-propylacetate (75% v / v, 225 ml) was loaded into the reactor, and when the internal temperature reached <6 ° C, the suspension was rinsed through the filter cake. The wet cake was then dried under vacuum at about 40 ° C for about 18 hours, providing C-1a.

[0578] ¹ H NMR (400 MHz, CDCl ^a ): 87.12 (br, 1H), 6.66 (ap t, J = 8.1 Hz, 2H), 4.50 (ap d, J = 5 , 7 Hz, 2H), 4.08 (s, 2H), 3.44 (s, 2H), 3.40 (s, 3H). ¹³ C NMR (100 MHz, CDCl ^a ): 8203.96, 164.90, 162.37 (ddd, J = 250.0, 15.7, 15.7 Hz), 161.71 (ddd, J = 250 , 3, 14.9, 10.9 Hz), 110.05 (ddd, J = 19.7, 19.7, 4.7 Hz), 100.42 (m), 77.58, 59.41, 45.71, 31.17 (t, J = 3.5 Hz). LCMS, calculated: 275.23, found: 275.97 (M).

N. Enamine formation of D-1a from C-1a

[0579]

[0580] C-1a (8.4 g, 1.0 equiv.) Was loaded into a reactor, followed by the addition of 2-methyltetrahydrofuran (166.7 ml, 20 volumes, 0.18 M) and trifluoroacetic acid ( 231.9 uL, 0.1 equiv.). The reaction mixture was heated to an internal temperature of approximately 40 ° C and DMF-DMA (3.0 ml, 0.75 equiv.) Was quickly added. The reaction mixture is stirred for a few minutes, followed by the addition of D-1a seeds (20 mg, 0.002 equivalents) at approximately 40 ° C. The heterogeneous mixture was aged at 40 ° C for approximately one hour. An additional portion of DMF-DMA (1.5 ml, 0.37 equivalents) was added and the reaction mixture was stirred for approximately 25 minutes. A final portion of DMF-DMA (1.5 ml, 0.37 equiv.) Was added, and the mixture of The reaction was cooled to about 40 ° C at room temperature and allowed to stir overnight.

[0581] The reactor contents were filtered and the filter cake was rinsed with a combination of 2-methyltetrahydrofuran and heptane solvents (67.1 ml, 8 volumes) to provide D-1a. ¹ H NMR (400 MHz, CDCh): 88.34 (br, 1H), 7.83 (s, 1H), 6.63 (m, 2H), 4.53 (s, 2H), 4.12 ( s, 2H), 3.34 (s, 3H), 3.10 (s, 6H). ¹³ C NMR (100 MHz, CDCl ^a ): 8 192.33, 165.85, 163.03, 160.54, 158.00, 110.89, 103.50, 100.05, 76.11, 58, 77, 44.74, 30.61. LCMS, calculated: 330.12, found: 330.91 (M).

O. Condensation and cyclization of D-1a to form F-1a through E-1a

[0582]

[0583] D-1a (70.0 g, 212 mmol, 1.0 equivalent) was loaded into an inert 1 L reactor. Methanol (420 ml, 6 volumes) and aminoacetaldehyde dimethylacetal (1.28.8 ml, 233 mmol, 1.1 equivalent) were then loaded into this reactor. The reactor envelope temperature was maintained between approximately 16 and 23 ° C.

[0584] After aging the reaction for approximately 1-2 hours, dimethyl oxalate ( 2.125 g, 1.06 mol, 5.0 equivalents) was charged into the reactor and the reactor envelope temperature increased to between approximately 42 - 48 ° C. After achieving complete dissolution of dimethyl oxalate, the reactor was charged with sodium methoxide as a solution in methanol (84.7 g, 25% by weight, 197 mmol, 1.85 equivalents). The reactor envelope temperature was maintained between about 42-48 ° C for about 14-18 h.

[0585] The reactor envelope temperature was reduced to approximately 34-37 ° C over the course of approximately 1 h. After reaching a stable temperature in this range, the reactor was charged with F-la seed crystals (0.350 g, approximately 0.5% by weight) and allowed to age for approximately 1-2 h. At this point, water (420 ml, 6 volumes) was loaded into the reactor over the course of about 2 to 3 hours. The reactor envelope temperature was reduced to approximately 18-22 ° C for approximately 1 h.

[0586] The resulting suspension was discharged from the reactor and the solids were collected by filtration. The liquors were recycled to displace the solids left in the reactor. The solids collected in the filter were then washed with a 1: 1 mixture of water and methanol (420 ml, 6 volumes), followed by water (420 ml, 6 V). The collected wet cake was dried in a vacuum oven at about 36-42 ° C for about 16 h, providing F-la.

[0587] ¹ H NMR (400 MHz, CDCl ^a ): 810.28 (t, J = 5.5 Hz, 1H), 8.38 (s, 1H), 6.66-6.53 (m, 2H ), 4.58 (d, J = 5.6 Hz, 2H), 4.43 (t, J = 4.7 Hz, 1H), 4.00 (d, J = 4.7 Hz, 2H), 3.92 (s, 3H), 3.88 (s, 3H), 3.32 (s, 6H). ¹³ C NMR (100 MHz, CDCh): 8 173.08, 163.81, 162.17, 162.14 (ddd, J = 249.2, 15.6, 15.6 Hz), 161.72 (ddd , J = 250.5, 15.0, 10.9 Hz), 149.37, 144.64, 134.98, 119.21, 110.53 (ddd, J = 19.8, 4.7, 4 , 7 Hz), 102.70, 100.22 (m), 60.68, 56.75, 55.61, 53.35, 30.64. LCMS, calculated: 458.39, found: 459.15 (M + H).

P. Acetal hydrolysis of F-1a to form FF-1a:

[0588]

[0589] To a solution of F-1a (10.0 g, 1.0 equivalent) and acetonitrile (50 mL) was added ptoluenesulfonic acid monohydrate (0.414 g, 0.10 equivalent) and acetic acid (16.3 mL, 12 equivalent). The reaction was then heated to approximately 75 ° C and aged for approximately 8-10 hours. Once the completion of the reaction was confirmed by HPLC, the reaction was cooled to room temperature and water (60 ml) was added. The mixture was then concentrated under reduced pressure to remove acetonitrile. The resulting suspension was aged then at room temperature for about 2 hours, it was filtered and washed with water (2 X 30 ml). The cake was dried in a vacuum oven at about 50 ° C for about 10 hours to give FF-1a.

[0590] ¹ H NMR (400 MHz, DMSO-d ^a ): 10.34 (t, J = 8.0 Hz, 1H), 8.45 (s, 1H), 7.19 (m, 2H), 6.37 (m, 2H), 4.96 (m, 1H), 4.55 (d, J = 4.0 Hz, 2H), 3.95 (m, 2H), 3.93 (s, 3H ). 3.79 (s, 3 H). ¹³ C NMR (100 MHz, DMSO-d ⁶ ): 8 172.32, 163.47, 162.10, 161.93 (dt, J = 246, 15.0 Hz), 161.41 (ddd, J = 247, 15.0, 11.0 Hz), 148.01, 145.57, 135.84, 118.32, 111.48 (td, J = 20.0, 5.0 Hz), 101.17 ( m), 87.99, 60.55, 60.50, 53.98, 30.37. LCMS, calculated: 431.1061, found: 431.1062 (M + H).

Q. Cyclization of FF-1a and N-1a.BzOH to form G-1a

[0591]

[0592] FF-1a (90.0 g, 1.0 equiv.), N-1a.BzOH (60.7 g, 1.3 equiv.) And potassium acetate (51.3 g, 2, 5 equiv.) In a reactor. Dichloromethane (DCM, 1.1 L) was charged and the mixture was stirred at approximately 20 ° C until the reaction was complete. A 5% aqueous solution of NaHCO ³ (540 ml) was charged into the reactor and the mixture was stirred until the solids dissolved completely. The phases were separated and the lower organic phase was reloaded into the reactor. Water (450 ml) was charged to the reactor and the mixture was stirred for approximately 15 minutes. The phases were separated and the organic phase was distilled to dryness.

[0593] The crude G-was dissolved in dimethylformamide (DMF, 180 ml) and the resulting solution was loaded into a reactor containing water (1.1 L) for approximately 2 hours, while the water was stirred. The product suspension was aged at approximately 20 ° C for approximately 12 hours and then filtered. The product cake was washed with water (360 ml) and dried to provide G-la.

[0594] ¹ H NMR (400 MHz, CDCl ^s ): 810.23 (t, J = 5.5 Hz, 1H), 8.39 (s, 1H), 6.60 (t, J = 8.1 Hz, 2H), 5.29 (dd, J = 9.5, 3.7 Hz, 2H), 4.57 (d, J = 5.4 Hz, 3H), 4.33 (dd, J = 12 , 8, 3.8 Hz, 1H), 4.02-3.87 (m, 1H), 3.94 (s, 3H), 2.06-1.88 (m, 4H), 1.78 ( dd, J = 17.2, 7.5 Hz, 1H), 1.55-1.46 (m, 1H). ¹³ C NMR (100 MHz, CDCl ^a ): 8174.53, 163.75, 162.33 (dd, J = 249.4, 15.7, 15.7 Hz), 161.86 (ddd, J = 250 , 4, 14.9, 10.9 Hz), 154.18, 154.15, 142.44, 129.75118.88, 110.58 (ddd, J = 19.8, 4.7, 4.7 Hz), 100.42 (m), 77.64, 74.40, 61.23, 54.79, 51.13, 38.31, 30.73, 29.55, 28.04. LCMS, calculated: 463.14, found: 464.15 (M + H).

R. Conversion of (-) - Vince lactam to B-1a

[0595]

[0596] Wet Pd / C (0.138 kg) was loaded into a reactor followed by 2-MeTHF (421 kg) and (-) - Lactamic Vince (55 kg). The vessel was purged with nitrogen followed by hydrogen. The contents were adjusted to approximately 25 to 35 ° C and the hydrogen was maintained at approximately 0.30 to 0.35 MPa. After approximately 6.5 h, the reaction was considered complete by HPLC. The contents were filtered through celite (11 kg) and washed with 2-MeTHF (102 kg). The product was obtained in solution.

[0597] A solution of Boc2O in 2-MeTHF was prepared as follows: Boc2O (123 kg) was loaded into a reactor followed by 2-MeTHF (60 kg). Once a solution was achieved, it was discharged into a container and rinsed with 2-MeTHF (44.6 kg) and maintained until later use.

[0598] The hydrogenation product solution was loaded into a reactor and concentrated under reduced pressure at about 5 to 6 V at <45 ° C. DMAP (0.34 kg) was loaded and the mixture was heated to approximately 45 to 50 ° C. The Boc2O solution was added for approximately 2 h and the mixture was allowed to stir for an additional 2 h at the desired temperature. After this time, the reaction was considered complete by HPLC. 2-MeTHF (480 kg) was charged and the solution was concentrated under reduced pressure at about 4 to 5 V at about <45 ° C. This process was repeated two more times to remove t-BuOH. 2-MeTHF (278.8 kg) was loaded to provide a-1a in solution.

[0599] The a-1a solution was diluted with 2-MeTHF (405.8 kg) and cooled to -10 to 0 ° C. MeMgBr (35% in 2 MeTHF, 201.3 kg) was added for about 6 h to maintain the temperature at about -10 to 0 ° C. After the addition was complete, the mixture was stirred for an additional 1 to 2 h, at which time the reaction was completed as determined by HPLC. 15% aqueous AcOH (350 kg) was added keeping the temperature between about 0 and 5 ° C to adjust the pH to about 7. The layers were separated and the organic layer was washed with water twice (726 kg of total water used). The organic layer was concentrated at about 4 to 5 V under reduced pressure at about <45 ° C. The solution was azeotropically distilled with 2-MeTHF three times at approximately 4 to 5 V each time (2810 kg of 2-MeTHF was used). The final solution was concentrated under reduced pressure to approximately 2.5 to 3 V. N-heptane (126 kg) was added slowly keeping the temperature between 30 and 35 ° C. B-1a seeds (0.7 kg) were added and the mixture was stirred at approximately 30 to 35 ° C for 5 to 10 h. Additional n-heptane (200.4 kg) was added keeping the temperature at about 30 to 35 ° C for about 5 h. The contents were distilled under reduced pressure at about <45 ° C to about 6 to 7 V. Additional n-heptane (243.2 kg) was added keeping the temperature at about 30 to 35 ° C for about 1 to 2 h. The contents were distilled under reduced pressure at about <45 ° C to about 6 to 7 V. Additional n-heptane (241.4 kg) was added maintaining the temperature at about 30 to 35 ° C for about 1 to 2 h. The contents were distilled under reduced pressure at about <45 ° C to about 6 to 7 V. Additional n- heptane (253.6 kg) was added keeping the temperature at about 30 to 35 ° C for about 1 to 2 h. The contents were cooled to about -5 to 0 ° C and held for about 1 to 2 h. The product was collected by filtration, washed with n-heptane (187 kg) at about -5 to 0 ° C, and dried under reduced pressure at about 40 to 45 ° C to provide the single enantiomer b-1a.

S. Conversion debB-1a to cc-1a

[0600]

[0601] B-1a (90.9 kg) and toluene (822 kg) were loaded into a reactor and stirred at a temperature of 25 to 30 ° C to achieve a solution. M-CPBA (174 kg) was loaded into the reactor in 5 portions (4 to 6 h between additions). The reaction was allowed to stir at about 25 to 30 ° C until the reaction was considered complete by HPLC (about 10 to 20 h). 20% NaHSO3 (428 kg) was added keeping the temperature approximately below 30 ° C and the mixture was stirred until it was negative with potassium iodide and starch paper. 10% NaOH (698 kg) was added keeping the temperature approximately below 30 ° C. The mixture was stirred for approximately 30 to 60 min. The organic layer was washed with water (500 kg) and the organic layer was concentrated under reduced pressure at about <45 ° C to 5 to 6 V. The temperature was adjusted to 15 to 25 ° C to provide the oxidized product in solution.

[0602] Water (90 kg), methanol (70 kg) and LOHH2O (29.5 kg) were added to the solution of the oxidized product and the mixture was stirred at a temperature of 25 to 30 ° C for 3 to 6 h, at which time the reaction was considered complete by HPLC. Toluene (390 kg) and 25% NaCl (278 kg) were added to the mixture and stirred for approximately 30 to 60 min. The layers were separated and 20% NaCl (259 kg) was added to the organic layer. The pH of the solution was adjusted to approximately 7 to 8 with 1 N HCl (7.6 kg) and the layers were separated. The organic layer was washed with 20% NaCl (259.4 kg). The organic layer was filtered and concentrated under reduced pressure at about <45 ° C to about 4.5 to 5.5 V. Toluene (385.6 kg) was charged and the distillation / toluene addition was repeated until KF <0 , 05%. Toluene (385.3 kg) was loaded followed by active carbon (6.5 kg). The mixture was heated to about 30 to 40 ° C and stirred for about 2 to 6 h. The contents were cooled, filtered through celite (6.3 kg) and washed with toluene (146 kg). The filtrate was concentrated under reduced pressure at about <45 ° C to about 1.5 to 1.6 V. The mixture was stirred for about 30 to 60 min at about 30 to 35 ° C. N-Heptane (87 kg) was charged for approximately 1 to 2 hours and the mixture was seeded with cc-1a (0.516 kg) and stirred for an additional 2 to 3 hours. The n-heptane (286.4 kg) was slowly loaded and stirred for approximately 2 to 3 h. The mixture was cooled to about 10 to 15 ° C and stirred for an additional 3 to 5 h. The product was collected by filtration and washed with n-heptane (40 kg) at approximately 10 to 15 ° C. The product was dried under reduced pressure at about 35 to 45 ° C to provide the single enantiomer cc-1a.

T. Classic resolution of c-1a

[0603]

[0604] A vessel was charged with C-1a (10.0 g, 1 equivalent), (S) -Naproxen (11.5 g, 1.03 mmol) and water (200 ml). The mixture was heated at reflux overnight, after which the mixture became dark. Solvent removal by rotary evaporation produced the desired salt as a brown solid. The mixture of dd-2a and dd-1a (3.0 g) was suspended in MEK (50 ml) and the mixture was heated to reflux. Water (4 ml) was added. The mixture was allowed to cool to room temperature. The solid was isolated by filtration, dried and recrystallized from 10% water in MEK (30 ml) to provide dd-1a which showed an optical purity> 90% ee.

U. Classic C-1a Resolution

[0605]

[0606] To a solution of c-1a (89.7 mg, 1.0 equiv.) In IPA (0.9 mL) a solution of S - (+) - mandelic acid (134.9 mgs,) was quickly added 1.0 equiv) in IPA (0.9 mL). The mixture was stirred at about room temperature and a solid precipitate was observed after about 20 minutes. The suspension was stirred for an additional 15 minutes, and the solids were filtered and collected. The solids obtained from the initial salt formation were recrystallized from IPA and slowly cooled from about 80 ° C to about 0 ° C to provide the danthine-enriched product dd-1b.

V. Enzymatic resolution of c-1a - Selective acylation

[0607]

[0608] Toluene (500 ml) was added to a reaction vessel followed by c-1a (50 g, 1 eq.). Glutaric anhydride (28.4 g, 1 eq.) Was added followed by Novozyme 435 (7.5 g, 15% by weight). The reaction was allowed to stir for about 23 h at about 10 to 15 ° C. Additional Novozyme (2.5 g, 5% by weight) was charged and the reaction was allowed to proceed for about 12 hours at about 10 to 15 ° C. The solids were removed by filtration and rinsed with toluene (100 ml). The organic phase was washed with 10% Na2CO3 (250 ml) followed by 5% Na2CO3 (250 ml). The combined aqueous phases were washed with MTBE (2 x 500 ml). THF (150 ml) was added to the resulting aqueous phase, followed by sodium hydroxide (14.9 g, 3 equivalents). The mixture was allowed to stir for about 4 h at about 15 at 20 ° C. The layers were separated and the THF layer was concentrated. The aqueous layer was extracted with dichloromethane (2 x 250 ml). The residue of the THF layer was dissolved in the combined dichloromethane and the mixture was washed with water (250 ml). The organic phase was concentrated. to about 100 ml and water (300 ml) was added. The mixture was further concentrated to about 250 ml at about 55 to 60 ° C. The mixture was cooled to about 47 ° C for about 1 h, product seeds (200 mg) were added and the mixture was aged for about 1 hour at about 45 to 47 ° C. The mixture was cooled to about 25 ° C for about 2 hours and aged for about 0.5 hours. The solids were collected by filtration and washed with water (50 ml). The product was dried at about 35 to 40 ° C under vacuum to provide the desired product cc-1a (> 95% ee).

W. Enzymatic Resolution of C-1a - Selective Hydrolysis

[0609]

[0610] A mixture of compound C-1a (50 g, 1 eq.), Glutaric anhydride (42.5 g, 1.5 eq.) And DMAP (50 mg, 0.001 eq.) In 300 ml of pyridine was stirred overnight at approximately 60 ° C. The reaction mixture was evaporated to dryness. Subsequently, the residue was dissolved in DCM (250 ml) and washed with 3 x 250 ml of 0.2 M HCl (aq.). The organic layer was evaporated to dryness. The residue was stirred with 300 ml of water and the pH was adjusted to 7.8 with approximately 300 ml of 2 M NaOH solution. The water layer was washed with DCM (3 x 70 ml). The aqueous layer was then acidified to pH 4 with 3 N HCl (aq.) And extracted with DCM (4 x 150 ml and 2 x 100 ml). The combined organic layers were dried over Na2SO4, filtered and evaporated, yielding a colorless oil that crystallized on standing. Trituration with pentane (~ 100 ml), followed by filtration and vacuum drying, produced racemic ee-1a.

[0611] Racemic ee-1a (1.008 g) was suspended in diisopropyl ether (10 ml). To the suspension was added 200 mM sodium phosphate buffer, pH 7 (20 ml) and Cal-B (0.2 g). The reaction mixture was stirred at 250 rpm, 30 ° C for ~ 100 h (> 80% ee observed after 91.5 h). The reaction mixture was filtered and the layers of the filtrate separated. The solid was washed with DCM (2 x 10 ml). The filtrate was used to extract the aqueous layer. The aqueous layer was extracted a second time with DCM (10 ml). The combined organic layers were washed with 5% Na2CO3 (2 x 20 ml) and brine (10 ml) and dried over Na2SO4. Filtration and evaporation of volatile compounds under reduced pressure provided the desired product cc-1a.

X. Allylic amination of F-1a to form G-1a

[0612]

[0613] Triphenylphosphine (0.37 g, 0.02 eq) and Pd2 (dba) 3 (0.32 g, 0.005 eq) were mixed in degassed THF (200 ml) at approximately room temperature for approximately 20 minutes. F-1a (10 g, 1 eq, single enantiomer), Cs2CO3 (46 g, 2 eq) and di-ferc-butyl iminodicarboxylate (16.05 g, 1.05 eq) were added and the mixture was heated to 50 ° C for approximately 18 h. The mixture was cooled and water (100 ml) and ethyl acetate (50 ml) were added. The layers were separated and the organic phase was washed 2 x ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated to dryness. The residue was purified by silica gel column chromatography (0 to 40% ethyl acetate in hexane). The isolated material was dissolved in MeTHF, washed with 5% aq. KOH, concentrated and purified by silica gel column chromatography (0 to 10% methanol in dichloromethane) to provide the desired product g-1a.

Y. Hydrogenation of G-1a to form h-1a

[0614]

[0615] G-1a (1.0 g) and PtO2 (0.008 g) were combined in isopropanol (10 ml). The vessel was washed with H2 gas and stirred under a hydrogen atmosphere at about room temperature for about 18 h. The mixture was filtered through celite and used without further purification in subsequent deprotection.

Z. Deprotection of h-1a to form N-1a

[0616]

[0617] Acetyl chloride (1.7 ml, 7 eq) was combined with isopropanol (5 ml) and stirred at approximately room temperature for approximately 15 minutes to generate HCl in isopropanol. The raw h-1a starting material in isopropanol (2.5 ml) was added and rinsed with isopropanol (2.5 ml). After about 18 h, the suspension was cooled to about 0 ° C and collected by N-1a filtration. The ¹ H NMR (CD ³ OD) confirmed that the desired product was isolated.

Claims (15)

1. A process for preparing a compound of Formula p-1J-1 according to the following scheme:

wherein the process comprises reacting the free acid of b-1 with approximately one to five equivalents of J-1; and where Hal is halogen, n is 1.2 or 3, and R ^a is (C ¹ -C ⁴ ) alkyl, aryl (C ⁶ -C ¹⁰ ) or aryl (C ⁶ -C ¹⁰ ) aryl (C ¹ -C ⁴ ). 2. The process of claim 1, wherein B-1 reacts with J-1 in the presence of an acid selected from the group consisting of an inorganic acid, an organic acid, a halogenated organic acid and mixtures thereof. 3. The method of claim 2, wherein the acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, trifluoromethanesulfonic acid, formic acid, trifluoroacetic acid, trichloroacetic acid, perfluoropropionic acid and a mixture thereof . 4. The process of claim 3, wherein the acid is trifluoroacetic acid. 5. The process of any one of claims 1 to 4, wherein J-1 is in the form of salt or co-crystal. 6. The process of any one of claims 1 to 5, wherein Hal is F. 7. The process of any one of claims 1 to 6, wherein J-1 is

8. The process of any one of claims 1 to 6, wherein J-1 is

9. The process of any one of claims 1 to 6, wherein J-1 is

10. A process to prepare a salt of formula p-1J-1

wherein the process comprises dissolving the free acid of B-1 and adding an equivalent of J-1, where Hal is halogen, n is 1, 2 or 3, R ^a is (C ¹ -C ⁴ ) alkyl, aryl (C ⁶ -C ¹⁰ ) or aryl (C ⁶ -C ¹⁰ ) aryl (C ¹ -C ⁴ ). 11. A compound that has the following structure:

12. A process for preparing a compound of formula C-1

wherein the process comprises reacting a compound of formula B-1J-1 with approximately 0.1 to 1 equivalent of a suitable acid, and where Hal is halogen, which can be the same or different, n is 1, 2 or 3, and R ^a is (C ¹ -C ⁴ ) alkyl, aryl (C ⁶ -C ¹⁰ ) or aryl (C ⁶ -C ¹⁰ ) aryl (C ¹ -C ⁴ ). 13. The method of claim 12, wherein the acid is selected from the group consisting of an inorganic acid, an organic acid, a halogenated organic acid, a Lewis acid and mixtures thereof. 14. The process of any one of claims 12 to 13, wherein the acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, trifluoromethanesulfonic acid, formic acid, trifluoroacetic acid, trichloroacetic acid, perfluoropropionic acid, dichloroacetic acid, chloroacetic acid, acetic acid, paratoluenesulfonic acid, methane sulfonic acid, zinc chloride, magnesium bromide, magnesium triflate, copper triflate, scandium triflate and a mixture thereof. 15. The process of any one of claims 12 to 14, wherein the acid is trifluoroacetic acid.